CN113117543B

CN113117543B - Buffer management and identification in a bioprocessing system

Info

Publication number: CN113117543B
Application number: CN202011623536.0A
Authority: CN
Inventors: M·B·西尔; D·G·埃尔顿; B·伊赛罗维克; J·B·劳滕巴赫
Original assignee: Pall Corp
Current assignee: Situofan Usa Ltd
Priority date: 2019-12-31
Filing date: 2020-12-31
Publication date: 2023-02-03
Anticipated expiration: 2040-12-31
Also published as: EP3845626A1; US20240142478A1; JP2021110740A; SG10202013222WA; US11899028B2; KR20210086568A; US20210199679A1; JP7071489B2; KR102544263B1; CN113117543A

Abstract

The present disclosure relates to buffer management and identification in a biological processing system. The buffer management system comprises at least one workstation configured to support a supply of concentrated buffer solution; and an inline dilution skid having a manifold and at least one workstation to support delivery of diluted (surge) buffer from the inline dilution skid. The latter station also supplies the bio-processing unit with ready-made (diluted) buffer. The manifold is in fluid communication with a supply of concentrated buffer solution and is adapted to be placed in fluid communication with a source of water for injection (WFI). The inline dilution skid is configured to variably mix the supply of concentrated buffer solution and the source of WFI to obtain a series of diluted buffer solutions. A process for automatically identifying the placement of buffer solutions in bioprocessing applications uses signals from various sensors to identify fluidic connections between components of a system.

Description

Buffer management and identification in bioprocessing systems

Cross Reference to Related Applications

This patent application claims priority from U.S. provisional patent application No.62/955,933 entitled "Buffer Management and Identification in Bioprocessing System" filed on 31.12.2019, which is incorporated herein by reference in its entirety.

Background

Buffer management systems typically include a plurality of biological container bags containing buffer solutions for bioprocessing applications. Conventional buffer management systems use a weight scale, typically a load cell, to determine the weight of the liquid in the biological container bag for level detection, which weight is transferred to an automated system. The weight detected by the weigh scale is converted into a calculated volume value using a conversion factor.

In conventional systems, buffer solutions are made at full strength and mass produced for storage in their respective tote bags (totes). For typical bioprocessing applications, multiple buffer solutions are used, where the requirement for each buffer solution is variable, in some cases the required amount of each buffer is about 2000 liters. The tote bag is then transported from the buffer preparation area to the processing kit. Thus, the bioprocessing process operation and its buffer preparation area with buffer carrier bags consumes a lot of space. Furthermore, for larger tote bags, specialized mobile equipment is sometimes required, which presents inherent risks.

The management of buffers for a given bioprocessing application may require a large number of tube connections. Typically, the management and inspection of these buffer connections is performed manually by the user and there is a significant risk of operator error (such as due to the wrong connection(s) being made), which can result in process delays and product loss.

There is a continuing need in the art to provide additional solutions to enhance the management of buffer solutions used in various bioprocessing applications. It will be appreciated that the present inventors have created this background description to aid the reader, and should not be taken as an indication that any of the indicated problems are themselves recognized in the art. While the described principles may, in some aspects and embodiments, alleviate problems inherent in other systems, it will be recognized that the scope of the claimed innovation is defined by the appended claims, rather than by the ability of any disclosed feature to solve any particular problem mentioned herein.

Disclosure of Invention

In one aspect, the present disclosure is directed to embodiments of a buffer management system for use in a biological processing system. In embodiments, the buffer management system may be used to create a plurality of buffers from a corresponding plurality of concentrated buffer solutions for use in bioprocessing applications.

In one embodiment, the buffer management system includes a collection of concentrated buffer solutions, an in-line dilution skid, and a control unit. The inline dilution skid includes a single-use manifold including a plurality of buffer inlet ports and a buffer characteristic sensor in fluid communication with each buffer inlet port. The plurality of buffer inlet ports are each in fluid communication with a different buffer solution in the set of concentrated buffer solutions. The buffer characteristic sensor is configured to detect a value of a buffer characteristic of a fluid flowing therethrough and generate a buffer characteristic signal indicative of the sensed value of the buffer characteristic.

The control unit includes a processor, a non-transitory computer readable medium carrying a buffer management program, and a data storage device operatively arranged with the processor. The processor is in electrical communication with the buffer characteristic sensor to receive the buffer characteristic signal therefrom. The processor was programmed with a buffer management program. The buffer management program has an identification module configured to automatically identify a concentrated buffer solution entering the manifold through one of the buffer inlet ports and passing through the manifold based on the buffer characteristic signal.

In another aspect, the present disclosure is directed to embodiments of a technique for automatically identifying the placement of a buffer solution in a bioprocessing application. In one embodiment, a method of using a buffer management system includes drawing one of a set of amounts of concentrated buffer solution into a first buffer inlet port of a plurality of buffer inlet ports of a manifold. The buffer characteristics of the concentrated buffer solution are sensed in the manifold. A buffer characteristic signal indicative of the value of the sensed buffer characteristic is transmitted to the control unit. The control unit is used to identify the concentrated buffer solution entering the manifold via the first buffer inlet port based on the buffer characteristic signal.

In another embodiment, a method of using a buffer management system includes draining a volume of liquid from a first buffer drain port of a plurality of buffer drain ports of a manifold into one of a plurality of biocontainers. The plurality of buffer fluid outlet ports are each in fluid communication with a different one of the plurality of biological containers. Sensing an amount of material stored within each of the plurality of biocontainers separately. Transmitting a fill level signal to the control unit, respectively, the fill level signal being indicative of a value of the amount of material sensed within each of the plurality of biocontainers. The control unit is used to identify the biocontainer with which the first buffer outlet port is in fluid communication based on a change in the fill level signal therefrom.

Further and alternative aspects and features of the disclosed principles will be understood from the following detailed description and drawings. As will be appreciated, the buffer management systems, dilution slides, and manifolds used in the buffer management systems disclosed herein can be implemented in other and different embodiments, and can be modified in various respects. Accordingly, it is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the scope of the appended claims.

Drawings

FIG. 1 is a perspective view of an embodiment of a buffer management system constructed according to the principles of the present disclosure including an embodiment of a manifold and a biological treatment unit constructed according to the principles of the present disclosure.

Figure 2 is another perspective view of the buffer management system of figure 1 from the side of its concentrated buffer.

Figure 3 is another perspective view of the buffer management system of figure 1 from the side of the buffer it dilutes.

Fig. 4 is a plan view of an embodiment of a biological container bag suitable for use in embodiments of buffer management systems constructed according to the principles of the present disclosure.

FIG. 5 is a top plan schematic view of an angled support member and a capacitive fill level sensor for use in an embodiment of a bio-container assembly of a buffer management system constructed in accordance with the principles of the present disclosure.

FIG. 6 is a side view of the angled support member and the capacitive fill level sensor of FIG. 5.

FIG. 7 is a front view of the manifold of FIG. 1 suitable for use in an embodiment of a buffer management system constructed according to the principles of the present disclosure.

FIG. 8 is a partial front view of an embodiment of a buffer management system constructed according to the principles of the present disclosure including an embodiment of an inline dilution skid constructed according to the principles of the present disclosure interposed between a concentrated buffer rack tower and a diluted buffer rack tower, illustrating a manifold in a flush position.

FIG. 9 is a partial schematic diagram of the hydraulic circuit of the buffer management system of FIG. 8 illustrating the manifold in a water for injection (WFI) priming position.

Figure 10 is the view shown in figure 8 of the buffer management system illustrating the manifold in a first buffer stabilization position.

FIG. 11 is the view shown in FIG. 8 of the buffer management system illustrating the manifold in a first buffer fill position.

Figure 12 is a view of the buffer management system as shown in figure 8 illustrating the manifold in a second buffer stabilization position.

FIG. 13 is the view shown in FIG. 8 of the buffer management system illustrating the manifold in a second buffer fill position.

FIG. 14 is the view shown in FIG. 8 of the buffer management system, illustrating the manifold in a first concentrated buffer discharge position.

FIG. 15 is the view shown in FIG. 9 of the hydraulic circuit of the buffer management system of FIG. 8, illustrating the manifold in a second concentrated buffer discharge position.

FIG. 16 is the view shown in FIG. 8 of the buffer management system, illustrating the manifold in the system exhaust position.

Figure 17 is a view, as shown in figure 14, of the buffer management system illustrating the manifold in a first concentrated buffer discharge position and suitable for use in an embodiment of a process following principles of the present disclosure that identifies an arrangement of different concentrated buffer solutions in fluid communication with a plurality of buffer inlet ports of the manifold of the buffer management system.

Fig. 18 is a view similar to fig. 11 of the buffer management system illustrating the manifold in a first buffer fill position and suitable for use in embodiments of a process following principles of the present disclosure that identify an arrangement of biological containers in fluid communication with a plurality of buffer outlet ports of the manifold of the buffer management system.

Fig. 19 is a schematic diagram of a biocontainer of a diluted buffer rack tower and a bioprocessing unit illustrating an embodiment of a process that identifies the placement of a biocontainer in fluid communication with multiple inlet ports of a bioprocessing unit following the principles of the present disclosure.

It should be understood that the drawings are not necessarily to scale and that the disclosed embodiments are illustrated by way of example and in partial views. In certain instances, details that are not necessary for an understanding of the present disclosure or that render other details difficult to perceive may have been omitted. It should be understood that the disclosure is not limited to the particular embodiments described herein.

Detailed Description

Embodiments of buffer management systems constructed in accordance with the principles of the present disclosure are suitable for use in bioprocessing systems. Embodiments of a buffer management system constructed in accordance with the principles of the present disclosure may include a supply of concentrated buffer solution, a dilution skid configured to selectively dilute the concentrated buffer solution such that the diluted buffer solution has predetermined buffer characteristics, and a diluted buffer solution storage assembly configured to store a volume of at least one diluted buffer solution therein for use in a selected bioprocessing application. In an embodiment, a dilution skid constructed in accordance with the principles of the present disclosure includes a single-use manifold.

Embodiments of buffer management systems constructed in accordance with the principles of the present disclosure may be used in biopharmaceutical environments, but may also be used in other industrial applications where different fluids, solutions, reagents and/or chemicals are stored for metering to a process station. Embodiments of buffer management systems constructed in accordance with the principles of the present disclosure may be used to selectively generate at least one buffer solution from a supply of concentrated buffer solution for use in downstream processing applications.

Embodiments of buffer management systems constructed in accordance with the principles of the present disclosure are configured as relatively compact storage solutions to achieve a range of different buffer solutions for intended use in bioprocessing applications. Embodiments of buffer management systems constructed in accordance with the principles of the present disclosure may include a supply of concentrated buffer solution, a dilution skid having a single-use manifold, and a plurality of bio-container bags stacked on a small footprint (particularly with respect to conventional workstations configured for use in similar bio-processing applications) for storing therein buffer solution diluted to a desired degree for use in a predetermined bio-processing application. Embodiments of a buffer management system constructed in accordance with the principles of the present disclosure may be used as an alternative to conventional systems that use relatively large storage totes for comparable bioprocessing applications.

An embodiment of a buffer management system constructed in accordance with the principles of the present disclosure is configured to produce a buffer solution by diluting a buffer concentrate with WFI (water for injection). It should be understood that WFI, as used herein and in embodiments according to the principles of the present disclosure, may also include any other liquid suitable for mixing with another liquid for either dilution purposes or any other suitable mixing operation. In an embodiment, a buffer management system constructed in accordance with the principles of the present disclosure is configured to produce a buffer solution using a buffer concentrate with a dilution factor in the range of five to twenty times to obtain a final diluted buffer solution.

Embodiments of buffer management systems constructed in accordance with the principles of the present disclosure are configured to receive concentrated buffer solutions (such as buffers having concentrations in the range between five and twenty times the desired buffer concentration) and mix them with a supply of WFI (water for injection) in variable proportions to obtain the desired buffer solution. The diluted buffer can be delivered to a storage area (such as a rack tower supporting a plurality of biological container bags used in a bioprocessing application (e.g., such as a chromatography/Tangential Flow Filtration (TFF) application) as needed.

In an embodiment, a manifold constructed in accordance with the principles of the present disclosure includes tubing, a single-use pump head, a sensor, and a connection configured to selectively mix at least one concentrated buffer solution with WFI for a given buffer characteristic (such as, for example, pH or conductivity) or a combination of two or more buffer characteristics to produce a diluted buffer solution within a predetermined tolerance. In an embodiment, a manifold constructed according to the principles of the present disclosure includes two single use pump heads, one for delivering at least one buffer concentrate and the other for delivering WFI to mix with the buffer concentrate within the manifold to produce a diluted buffer solution according to a predetermined buffer formulation. In an embodiment, the manifold is arranged with a control unit of the dilution skid to provide automated operation of the buffer management system by changing pump speed/ratio, e.g. in response to at least one sensor feedback loop, to obtain a desired buffer formulation from a library of multiple buffer formulations, to selectively operate the control valves according to a predetermined sequence of operations, and to interface with other operational units in response to a demand for buffer solution.

In an embodiment, a manifold constructed according to the principles of the present disclosure includes a plurality of buffer inlet ports, a WFI inlet port, a pair of single use pump heads, at least one buffer characteristic sensor, a plurality of buffer discharge ports corresponding to the number of buffer inlet ports, and a waste outlet port. In an embodiment, a manifold constructed in accordance with the principles of the present disclosure includes a tubing arrangement configured to interact with a plurality of control valves such that a control unit can operate the control valves to close, open, or redirect liquid flow through the manifold to perform various buffer management sequences.

Turning now to the drawings, there is shown in FIGS. 1-3 an embodiment of a buffer management system 20 constructed in accordance with the principles of the present invention, including a dilution skid 30 constructed in accordance with the principles of the present invention, the dilution skid 30 including a single-use manifold 23. In an embodiment, the buffer management system 20 may include at least one embodiment of a manifold 23 constructed in accordance with the principles of the present disclosure. The illustrated buffer management system 20 is configured to receive different concentrated buffer solutions, such as buffer solutions in a range between five and twenty times the concentration of the buffer solution for a desired bioprocessing application in the bioprocessing unit 24, and then mix them sequentially with WFI (water for injection) in variable proportions to achieve the desired buffer. The buffer management system 20 may be configured to store the diluted buffer solution for delivery to and use by bioprocessing applications such as chromatography, tangential Flow Filtration (TFF), etc. performed on demand in the bioprocessing unit 24. In an embodiment, the diluted buffer solution may be stored in a plurality of biocontainer assemblies 25.

In an embodiment, the buffer management system 20 includes at least one

workstation

22, 26, 27 configured to support a supply of concentrated buffer solution, at least one

workstation

28, 29 configured to store diluted buffer solution made from a supply of concentrated buffer solution, which may be stored in the biocontainer assembly 25, an in-line dilution skid 30 having a single-use manifold 23. In an embodiment, the buffer management system 20 comprises a single-use system configured to generate multiple buffers from a concentrated buffer solution. In an embodiment, buffer management system 20 includes a plurality of

workstations

22, 26, 27 configured to support a plurality of different concentrated buffers and a plurality of

workstations

28, 29 configured to hold a plurality of surge biocontainer assemblies 25, surge biocontainer assemblies 25 configured to store corresponding diluted buffer solutions made from different supplies of concentrated buffer solutions via an inline dilution skid 30.

In the illustrated embodiment, the buffer management system 20 includes three concentrated buffer rack towers 22, 26, 27 configured to hold different supplies of concentrated buffer solution, an inline dilution skid 30 configured to generate a plurality of diluted buffer solutions for use in a biological processing application in the biological processing unit 24, and a pair of diluted buffer rack towers 28, 29 configured to hold a supply of diluted buffer solutions. In other embodiments, the buffer management system 20 may include different equipment configured to hold a supply of concentrated buffer and/or diluted buffer. For example, in other embodiments, a buffer management system 20 constructed in accordance with the principles of the present disclosure may include at least one

tower

22, 26, 27 configured to hold one or more biological container assemblies filled with concentrated buffer. In other embodiments, a buffer management system constructed in accordance with the principles of the present disclosure may include at least one

column

28, 29 configured to hold one or more canisters filled with diluted buffer.

Referring to fig. 2, the three concentrated

buffer tower columns

22, 26, 27 of the buffer management system 20 are shown to have a similar configuration. Each of the illustrated concentrated buffer tower towers 22, 26, 27 includes a cart 32, a frame structure 34, and a pair of biocontainer tote bags 37. The frame structure 34 is mounted to the cart 32 and is configured to support a pair of biocontainer bags 37 in stacked relation. The concentrated buffer rack towers 22, 26, 27 include workstations configured to hold concentrated buffer solution for selective delivery to the inline dilution skid 30.

The cart 32 includes a base 40 and a plurality of wheels 41 rotatably attached to the base 40. In the illustrated embodiment, the base 40 is rectangular and a wheel 41 is rotatably attached at each corner of the base 40. In an embodiment, the base 40 may be substantially square. The base 40 of the cart 32 is mounted to the bottom 43 of the frame structure 34.

The frame structure 34 is connected to the cart 32. The frame structure 34 includes: a plurality of uprights 45 connected to the trolley 32 and in a mutually spaced relationship; and a plurality of cross members 47 extending between two of the columns 45 so that the frame structure 34 can support biological container totes 37 in vertically stacked relation to one another. In the illustrated embodiment, each concentrated

buffer rack tower

22, 26, 27 is configured to support two biocontainer totes 37 in a stacked relationship. In other embodiments, the concentrated buffer rack towers 22, 26, 27 may be configured to support different numbers of biocontainer totes 37, including a single biocontainer tote 37.

Each bio container bag 37 is fluidly connected to the manifold 23 of the inline dilution skid 30 via respective

flexible tubing lines

61, 62, 63, 64, 65, 66 extending between each bio container bag 37 and the manifold 23. In particular, tubing extends between each biocontainer bag 37 and a respective one of a plurality of

buffer inlet ports

121, 122, 123, 124, 125, 126 of manifold 23. The water supply line 67 may be in fluid communication with a supply of WFI (water for injection) such that the water supply line 67 extends between the supply of WFI and the WFI inlet port 127 of the manifold 23. In embodiments, the

flexible tubes

61, 62, 63, 64, 65, 66 may be made of any suitable material, such as silicone, thermoplastic elastomer (TPE), and the like. In an embodiment, the

conduits

61, 62, 63, 64, 65, 66 are adapted to be selectively blocked by pinch valves externally mounted thereon.

In other embodiments, the concentrated buffer rack towers 22, 26, 27 of a buffer management system constructed in accordance with the principles of the present disclosure may have different configurations. For example, in an embodiment, the concentrated buffer rack tower may include a plurality of biocontainer assemblies as described below in relation to the diluted buffer rack towers 28, 29 having "2D" (or "two-dimensional") biocontainer bags, as understood in the art.

Referring to fig. 3, a pair of

dilute buffer tower

28, 29 of the buffer management system 20 have a similar configuration. Each of the

dilute buffer tower

28, 29 shown includes a cart 32, a frame structure 34, and a plurality of biocontainer assemblies 25. A frame structure 34 is mounted to the cart 32 and is configured to support a plurality of biocontainer assemblies 25. The

dilute buffer tower

28, 29 comprises a workstation configured to hold a biocontainer 25, the biocontainer 25 configured to act as a surge container.

The frame structure 34 may support a plurality of bag fill level assemblies 35 in vertically stacked relation to one another. In the illustrated embodiment, each

dilute buffer tower

28, 29 is configured to support four bag fill level assemblies 35 in vertically stacked relation to one another. In other embodiments, the dilute buffer rack towers 28, 29 may be configured to support different numbers of bag fill level assemblies 35, including a single bag fill level assembly 35. The bag fill level assembly 35 may include a level sensor that feeds back to the automated control unit 100 of the dilution skid 30.

In the illustrated embodiment, each

dilute buffer tower

28, 29 is configured to support up to four biocontainer assemblies 25 in a stacked relationship. In other embodiments, the

dilute buffer tower

28, 29 may be configured to support a different number of biocontainer assemblies 25, including a single biocontainer assembly 25.

In an embodiment, each of the biocontainer assemblies 25 includes at least one biocontainer 55 (see fig. 4) fluidly connected to the manifold 23 of the inline dilution skid 30 via respective flexible tubing lines 91, 92, 93, 94, 95, 96 extending between each biocontainer 25 and the manifold 23 and between each biocontainer assembly 25 and the bioprocessing unit 24. In particular, a

conduit

91a, 92a, 93a, 94a, 95a, 96a extends between each biocontainer 25 of the diluted

buffer tower

28, 29 and a respective one of the plurality of

discharge ports

131, 132, 133, 134, 135, 136 of the manifold 23. A

conduit

91b, 92b, 93b, 94b, 95b, 96b extends between each bio-container 25 of the

dilute buffer tower

28, 29 and the bio-processing unit 24 for use by the bio-processing unit 24 as needed to perform a bio-processing application. The waste line 97 may be in fluid communication with the waste port 137 of the manifold 23 such that the waste stream may be discharged from the manifold to a suitable location (e.g., a separate tank or discharge system). In embodiments, the flexible tubes 91, 92, 93, 94, 95, 96, 97 may be made of any suitable material, such as silicone, TPE, and the like. In an embodiment, the conduits 91, 92, 93, 94, 95, 96, 97 are adapted to be selectively obstructed by pinch valves externally mounted thereto.

Referring to fig. 4-6, in an embodiment, each biocontainer assembly 25 includes a support member 50 in the form of an angled shelf mounted to the frame structure 34 of one of the diluted buffer shelf towers 28, 29, an electronic fill level sensor 52, and a biocontainer bag 55. In an embodiment, angled support member 50 includes a support surface 57, the support surface 57 configured to support biological container bag 55 in an inclined storage position relative to horizontal axis HA. In the illustrated embodiment, the frame structure 34 of each diluted

buffer tower

28, 29 includes a series of angled shelves 50 that are inclined at an inclination angle θ relative to the horizontal axis HA. The lower edge of each shelf 50 is positioned at the front end of the frame structure 34. The upper edge of each shelf 50 is positioned at the rear end of the frame structure 34 in opposing relation to the front end of the frame structure 34.

In an embodiment, the fill level sensor 52 is configured to generate a fill level signal indicative of a volume of material within the storage volume of the biocontainer bag 55 detected by the fill level sensor 52. In an embodiment, the fill level sensor 52 comprises a capacitive fill level sensor.

Referring to fig. 4, in an embodiment, biological container bag 55 comprises any suitable container configured to store a predetermined volume of material for use in an intended application. In an embodiment, biocontainer bag 55 comprises a "2D" (or "two-dimensional") biocontainer bag, as understood in the art, wherein the width W and length L of biocontainer bag 55 determine how the fill level moves up in biocontainer bag 55 and is detected by level sensor 52.

In the illustrated embodiment, the biocontainer bag 55 comprises a 2D biocontainer bag made of a flexible film material. The biocontainer bag 55 may include two or

more ports

85, 86 and tubing having connector ends configured to receive material within the interior storage volume of the bag 55 and/or to discharge material from the bag 55. In other embodiments, the biocontainer bag 55 includes at least one other port configured to serve as a sampling port. In an embodiment, for example, the biocontainer bag 55 may define a storage volume therein of a predetermined size, such as one hundred liters. In other embodiments, the storage volume may be a different size. In embodiments, biocontainer bag 55 comprises a suitable commercially available single use biocontainer bag such as, for example, available under the trade name Allegro ^TM 2D biocontainer bags are those available from Pall corporation of washington port, new york.

In an embodiment, the biocontainer bag 55 may include at least a pair of flexible panels 81 connected together. The flexible panels 81 cooperate together to define an internal storage volume configured to hold a predetermined volume of material (e.g., one hundred liters). In an embodiment, each panel 81 is made of a suitable plastic material. For example, in an embodiment, each panel 81 is made of Low Density Polyethylene (LDPE) fluid contacts and an outer film having an ethylene-vinyl alcohol copolymer (EvOH) gas barrier inner film. In an embodiment, biocontainer bag 55 may be made of a material that meets at least one of the following requirements: USP <88> in vivo bioresponse test for grade VI-50 ℃ plastics with the aim of monitoring the effect of biocontainer extracts on systemic toxicity, tissue irritation and biocompatibility of implantation; USP <87> bioresponse test (in vivo) (cytotoxicity) of plastics; and ISO 10993Biological Evaluation of a Medical Devices (section 8.2.2: ISO 10993Biological Evaluation of Medical Devices) in section 4 (hemolysis), section 5 (cytotoxicity), section 6 (implant test), section 10 (irritation and sensitization test) and section 11 (acute systemic toxicity).

Referring to fig. 5 and 6, in an embodiment, each rack 50 is configured to support a biological container bag 55 of a predetermined size. The angled support 50 includes a support surface 57, the support surface 57 being configured to support the biocontainer bag 55 in an inclined storage position relative to the horizontal axis HA. In embodiments of biocontainer assembly 25, capacitive fill level sensor 52 is mounted to support member 50 in any suitable manner that allows fill level sensor 52 to detect the volume of material stored in biocontainer bag 55 supported by support member 50. The capacitive fill level sensor 52 may be mounted to the angled support member 50 such that the capacitive fill level sensor 52 is positioned to detect the volume of liquid disposed within the bio-container bag 55 when the bio-container bag 55 is in the tilted storage position over a range of liquid volumes between a predetermined minimum fill volume and a maximum predetermined fill volume.

The support surface 57 of the stand 50 is substantially flat and is disposed at an inclination angle θ with respect to the horizontal axis HA. In the illustrated embodiment, the tilt angle θ is twenty-five degrees. In an embodiment, the inclination angle θ of the support member 50 of the bio-container assembly may vary. In an embodiment, the support surface 57 of the support member 50 of the biocontainer assembly may be disposed at an inclination angle θ relative to the horizontal axis HA, wherein the inclination angle θ is in a range between five and forty-five degrees, in other embodiments between ten and forty degrees, in still other embodiments between fifteen and thirty-five degrees, and in still other embodiments between twenty and thirty degrees. In an embodiment, the support surface 57 of the support member 50 of a biocontainer assembly constructed in accordance with the principles of the present disclosure may be deployed at an inclination angle θ relative to a horizontal axis, where the inclination angle θ is in a range between twenty and twenty-eight degrees, and in still other embodiments between twenty-two and thirty degrees. In embodiments, for example, the support member 50 may be made of any suitable material, such as a suitable plastic or metal.

One of ordinary skill in the art will recognize that the tilt angle may be varied depending on the particular parameters of the application in which the biocontainer assembly is intended to be used. For example, a shallow angle may be used in applications where the range of liquid volumes desired to be monitored is less than the maximum fill volume of a biocontainer bag used in the biocontainer assembly. Steeper tilt angles may be used in embodiments where the resolution of the fill level sensor bar 52 is enhanced and/or it is desirable to monitor smaller volume changes.

In an embodiment, each shelf 50 has at least one electronic fill level sensor 52 associated therewith. In an embodiment, the fill level sensor 52 is configured to generate a fill level signal indicative of an amount of material within the storage volume of the biocontainer bag 55 detected by the fill level sensor 52. In an embodiment, the capacitive fill level sensor 52 may be used to measure the fill level of a fluid medium or solid material disposed within the storage volume of the biocontainer bag 55. In an embodiment, the capacitive fill level sensor 52 may be a suitable commercially available strip sensor, such as those available from Balluff ltd. In an embodiment, the capacitive fill level sensor 52 for measuring the fill level may be configured to measure the impedance in response to the detected proximity of the material stored in the bio-container bag 55, the ohmic component of the bio-container bag 55, and in particular the capacitive component thereof, reflecting the measurement of the fill level of the material within the bio-container bag 55, and the measurement may be used to generate a fill level signal.

In an embodiment, the capacitive fill level sensor 52 comprises an electrode unit with a strip-shaped measuring electrode, a strip-shaped counter electrode and a strip-shaped shielding electrode. In an embodiment, the shield electrode at least partially surrounds the measurement electrode. A first AC voltage source having a predefined frequency and amplitude is provided, to which the shielding electrode is connected such that a shielding capacitor formed between the shielding electrode and the measuring electrode has a shielding capacitance proportional to the length of the shielding electrode. A second AC voltage source is provided having an equal frequency and a predefined second amplitude. The second amplitude is in phase opposition to the first amplitude, and the counter electrode is connected to an AC voltage source such that a measurement capacitor formed between the counter electrode and the measurement electrode has a measurement capacitance proportional to the filling level. The measuring electrode voltage present on the measuring electrode is used to determine the filling level. In an embodiment, in other respects, the Capacitive Fill Level Sensor 52 may be similar to that disclosed in U.S. patent application publication No. US2016/0047683, entitled "Capacitive Fill Level Sensor," which is incorporated by reference herein in its entirety.

In an embodiment, the filling level sensor 52 may be mounted directly to the support surface 57 of the stand 50. In still other embodiments, the fill level sensor 52 may be mounted to the bottom side of the support member 50.

In other embodiments, the capacitive fill level sensor 52 may be replaced by a plurality of fill level sensors arranged in a matrix and positioned at discrete locations corresponding to a desired control sequence. In an embodiment, the plurality of fill level sensors may operate as switch-type sensors that provide fill level signals indicative of a volume of liquid within the biocontainer bag 55, which may be used to manage buffer solutions (e.g., maximum fill position, minimum fill position, and operational fill level).

In embodiments, biocontainer assembly 25 may be varied depending on the maximum volume requirements of the biocontainer. In other embodiments, the rack 50 may be configured to support a plurality of biocontainer bags 55, each such biocontainer bag 55 having associated therewith a respective electronic fill level sensor 52 mounted to the rack 50.

In other embodiments, biocontainer assembly 25 includes a different type of fill level sensor. For example, in other embodiments, the bio-container assembly 25 may include a weight scale to determine the weight of the buffer solution within a respective one of the bio-container bags 55. The measured buffer solution weight can be converted into a volume measurement of this liquid. In an embodiment, the weight scale includes a suitable load cell that generates an electrical signal indicative of the measured weight.

Referring to fig. 1, inline dilution skid 30 includes cart 138, cabinet 139, and single-use manifold 23. The cabinet 139 is mounted on top of the cart 138 and is configured to house the hydraulic and automated equipment of the buffer management system 20. The manifold 23 comprises a single-use manifold that is removably mounted to the cabinet 139 such that the manifold 23 is in an operable arrangement with hydraulic and automated equipment within the cabinet 139.

The cart 138 includes a base 140 and a plurality of wheels 141 rotatably attached to the base 140. In the illustrated embodiment, the base 140 is rectangular and a wheel 141 is rotatably attached at each corner of the base 140. In an embodiment, the base 140 may be substantially square.

The cabinet 139 is mounted to the base 140 of the cart 138. In an embodiment, the cabinet 139 includes a storage unit for automated equipment and is made of, for example, a suitable metal (such as stainless steel). Cabinet 139 defines an interior cavity 143 and has an exterior surface 144. In an embodiment, cabinet 139 houses therein control unit 100 and a pair of pumps, including buffer pump 145 and WFI pump 147. A plurality of hydraulic control valves 151-167 (see fig. 7) may also be supported by the cabinet 139.

Referring to fig. 1, buffer pump 145 and WFI pump 147 are disposed within interior cavity 143 of cabinet 139. Single-use manifold 23 is removably mounted to an outer surface 144 of cabinet 139 such that manifold 23 is operatively arranged with a buffer pump 145 and a WFI pump 147.

In an embodiment, manifold 23 is configured to be operably arranged with buffer pump 145, WFI pump 147 and control unit 100 stored within cabinet 139, and with control valves 151-167 (see fig. 7). The manifold 23 is configured to selectively mix a supply of at least one concentrated buffer solution with a supply of WFI to produce a buffer solution having desired buffer characteristics for bioprocessing applications. After use in the intended bioprocessing application, the manifold 23 may be disconnected from the cabinet 139 of the inline dilution skid 30 and replaced with another single-use manifold of similar construction.

Referring to fig. 1, the pumps 145, 147 are in operable relationship with the control unit 100 such that the control unit 100 can selectively operate the pumps 145, 147. Buffer pump 145 is configured to deliver a supply of at least one concentrated buffer stored in

concentrated buffer tower

22, 26, 27 through manifold 23, and WFI pump 147 is configured to deliver a supply of WFI through manifold 23. In embodiments, pumps 145, 147 may be any suitable pump capable of producing a flow of liquid that meets the specifications of the intended application. In an embodiment, buffer pump 145 and WFI pump 147 include variable displacement pumps.

In embodiments, the buffer concentrate may be prepared in an intensity range of five to at least twenty times or more. Accordingly, WFI is pumped proportionally in a larger volume than the buffer concentrate(s) in order to achieve the desired diluted buffer formulation. Thus, in an embodiment, buffer pump 145 and WFI pump 147 are sized to meet the respective specified flow requirements of the various diluted buffer formulations intended for use with buffer management system 20. In embodiments, the buffer management system 20 is configured to produce up to 1200 liters per hour, but varying system sizes may be provided in other embodiments.

Control unit 100 is in electrical communication with buffer pump 145 and WFI pump 147. The control unit 100 is configured to selectively operate the buffer pump 145 and the WFI pump 147. In the illustrated embodiment, control unit 100 is configured to operate buffer pump 145 and WFI pump 147 independently. In an embodiment, the control unit 100 is configured to control at least one of the pump speed and the volumetric displacement of at least one of the buffer pump 145 and the WFI pump 147 to adjust the volumetric ratio of the buffer solution to the amount of water for injection (WFI) mixed together in the manifold 23.

The control unit 100 is configured to selectively operate the pumps 145, 147 to provide a plurality of buffer management operations according to at least one input signal received from the manifold 23 and bio-container assembly 25 of the diluted buffer rack towers 28, 29. In an embodiment, the control unit 100 is configured to operate the in-line dilution skid 30 to perform at least one buffer management sequence.

Referring to fig. 3, in an embodiment, the control unit 100 includes a controller 104, a processor 107, a non-transitory computer readable medium 108 with a buffer management program, a data storage device 109, and a display device 110. For example, the controller may be configured to selectively operate at least one component of buffer management system 20 (such as buffer pump 145 and WFI pump 147). The controller is in an operable communication arrangement with the processor 107. The processor 107 and the non-transitory computer readable medium 108 are in an operable arrangement to execute a buffer management program contained thereon. The processor 107 is operably arranged with the display device 110 to selectively display output information from the buffer management program and/or receive input information from a graphical user interface displayed by the display device 110.

In an embodiment, the controller 104 may include a user input and/or interface device having one or more user-actuated mechanisms (e.g., one or more buttons, a slider bar, a rotatable knob, a keyboard, and a mouse) adapted to generate one or more user-actuated input control signals. In embodiments, the controller 104 may be configured to include one or more other user-actuated mechanisms to provide various other control functions for the buffer management system, as will be appreciated by those skilled in the art. The controller 104 may include a display device adapted to display a graphical user interface. In embodiments, the graphical user interface may be configured to function as both a user input device and a display device. In an embodiment, the display device may comprise a touch screen device adapted to receive input signals from a user touching different parts of the display screen. In embodiments, the controller 104 may be in the form of a smartphone, tablet, personal digital assistant (e.g., wireless, mobile device), laptop, desktop, or other type of device. In an embodiment, the controller 104 and the processor 107 may comprise the same set of devices or equipment.

In an embodiment, the processor 107 comprises a specially programmed processor that can be used to determine whether the buffer solution produced by the inline dilution skid is within a predetermined tolerance given the desired buffer solution based on the buffer solution data sent by the manifold 23 to the processor 107. In the illustrated embodiment, the processor 107 is in an operative arrangement with the controller 104 to facilitate control and operation of the buffer management system 20. In an embodiment, the processor 107 may be configured to receive input signals from the controller 104, to transmit input control signals to the controller 104, and/or to transmit output information to the controller 104. In an embodiment, the controller 104 and the processor 107 may comprise the same device.

In an embodiment, at least one

sensor

171, 172, 173 is associated with the discharge line 183 of the manifold 23 and is configured to sense a value of a buffer characteristic (such as conductivity or pH, for example) or a fluid parameter to generate a signal indicative of the sensed value for the buffer characteristic/fluid parameter and transmit the signal to the control unit 100. In an embodiment, the control unit 100 may use the received signals to control the operation of the buffer management system 20. Each

sensor

171, 172, 173 is in electrical communication with the control unit 100 to transmit a respective signal thereto. In an embodiment, control unit 100 is configured to control operation of at least one of buffer pump 145 and WFI pump 147 based on signals received from at least one

such sensor

171, 172, 173.

In embodiments, the

sensors

171, 172, 173 may be any suitable sensor configured to detect a parameter of the buffer solution. In embodiments, the buffer parameters may be used to determine whether the generated buffer solution is within a specified tolerance range of a desired buffer solution and/or within a desired operating range of desired fluid characteristics. In the illustrated embodiment, single-use manifold 23 includes a conductivity sensor 171, a pressure sensor 172, and a pH sensor 173 disposed in discharge line 183 of manifold 23 and configured to transmit conductivity, pressure, and pH signals, respectively, to control unit 100. In an embodiment, the buffer management program may use at least one of the conductivity signal and the pH signal to determine whether the buffer solution passing through the discharge line is within a predetermined tolerance range of a given specification of a desired buffer. In an embodiment, the buffer management program may use the pressure signal to determine whether the manifold 23 is operating below a predetermined maximum pressure for safe operation.

The processor 107 is operatively arranged with the manifold 23 to receive buffer solution data therefrom and with the dilute buffer rack towers 28, 29 to receive buffer solution usage data therefrom. Although one electrical communication line is shown extending between the processor 107 and the dilute buffer rack towers 28, 29, it should be understood that in embodiments, each biocontainer assembly of the dilute buffer rack towers 28, 29 may be in independent communication with the processor 107. In an embodiment, the processor 107 is in electrical communication with the manifold 23, the dilute buffer rack towers 28, 29, and the concentrated buffer rack towers 22, 26, 27 via any verification technique, including wired communication channels. In an embodiment, throughout the buffer management system 20, the processor 107 is in electrical communication with at least one of the manifold 23, the

dilute buffer tower

28, 29, and the

concentrated buffer tower

22, 26, 27 via a wireless communication network including Wi-Fi networks and internet of things (IoT) devices.

In an embodiment, the processor 107 is configured to display the buffer solution data received from the manifolds and/or

racks

22, 26, 27, 28, 29 in the display device 110. The buffer solution data may also be stored in a data storage device 109 operably disposed with the processor 107 and/or the buffer solution data may be correlated with predetermined buffer characteristics (such as, for example, its pH) to identify the buffer solution passing through the manifold and/or to determine whether the buffer solution produced through the manifold is within a predetermined tolerance of the desired buffer solution.

In embodiments, the processor 107 may include any suitable computing device, such as a microprocessor, mainframe computer, digital signal processor, portable computing device, personal organizer, device controller, logic device (e.g., a programmable logic device configured to perform processing functions), digital Signal Processing (DSP) device, or a compute engine within an appliance. In an embodiment, the processor 107 also includes one or more additional input devices (e.g., a keyboard and mouse or other suitable human-machine interface (HMI)).

The processor 107 may have one or more memory devices associated therewith to store data and information. The one or more memory devices may comprise any suitable type, including volatile and non-volatile memory devices, such as RAM (random access memory), ROM (read only memory), EEPROM (electrically erasable programmable read only memory), flash memory, and the like. In one embodiment, the processor 107 is adapted to execute programs stored on a non-transitory computer readable medium to perform various methods, processes, and modes of operation in accordance with the principles of the present disclosure.

The buffer management program is configured to determine whether the buffer solution produced by the manifold 23 is within a given predetermined tolerance of the desired buffer solution based on the measurement signals received by the processor 107 from the manifold 23. In an embodiment, the buffer management program is configured to use the pH signal from the pH sensor 173 of the manifold 23 to determine whether the buffer produced is within a predetermined tolerance of the nominal specification provided for a given desired buffer. In an embodiment, the buffer management program is configured to use the conductivity signal from the conductivity sensor 171 of the manifold 23 to determine whether the buffer produced is within a predetermined tolerance of the nominal specifications provided for a given desired buffer.

In an embodiment, the non-transitory computer readable medium 108 may contain a buffer management program configured to implement an embodiment of a method of managing a buffer solution according to the principles of the present disclosure. In an embodiment, the buffer management program includes a graphical user interface that may be displayed by the display device 110. A graphical user interface may be used to facilitate user input of commands and data to the buffer management program and display of output generated by the buffer management program.

The buffer management program may be stored on any suitable computer readable storage medium. For example, in an embodiment, a buffer management program following principles of the present disclosure may be stored on a hard disk drive, a floppy disk, a CD-ROM drive, a tape drive, a zip drive, a flash drive, an optical storage device, a magnetic storage device, or the like.

In an embodiment, the pH and conductivity data from the manifold 23 may be displayed by the buffer management program via a graphical user interface in the display device 110. In an embodiment, the operator may set a predetermined tolerance range for pH and/or conductivity, and the buffer management program may be configured to generate an alarm when at least one of the measured pH and conductivity falls outside the predetermined tolerance range. In embodiments, the alarm may be any suitable alarm, including an audible signal and/or a warning message displayed via a graphical user interface on the display device 110.

In an embodiment, the processor 107 is in operable communication with a data storage device 109, the data storage device 109 comprising at least one database containing buffer solution data. In an embodiment, the buffer management program may be configured to store the measurement data generated by the manifold and the buffer solution data generated by the rack tower in the data storage device 109. In an embodiment, the measurement data and buffer solution usage data may be logically associated with time data in a data storage device such that various data may be retrieved at a given time.

Referring to FIG. 7, there is shown an embodiment of a manifold 23 constructed in accordance with the principles of the present disclosure that is suitable for use in an embodiment of a buffer management system 20 constructed in accordance with the principles of the present disclosure. The manifold 23 shown in fig. 7 comprises a single-use in-line buffer dilution manifold. The manifold 23 is configured to be removably mounted to the in-line dilution skid 30 of the buffer management system 20 of figure 1. In the illustrated embodiment, the manifold 23 includes replaceable parts that are installed once in the in-line buffer slide 30 for bioprocessing applications and then disassembled for disposal.

In the illustrated embodiment, manifold 23 comprises a piping arrangement having a buffer inlet line 181, a WFI inlet line 182, a discharge line 183, and a waste line 184. Tubing arrangements interconnect the various ports 201-207, 211-217 of manifold 23 and are associated with control valves 151-167 to control the flow of buffer solution and WFI through manifold 23. In an embodiment, the pipe arrangement comprises a plurality of flexible pipe lines. In embodiments, the flexible tubing may be made of any suitable material (such as silicone, TPE, etc.). In an embodiment, buffer inlet line 181, WFI inlet line 182, drain line 183, and waste line 184 comprise tubing adapted to be selectively blocked by a pinch valve externally mounted thereto.

The buffer inlet line 181 is in fluid communication with the mixing junction 185. The WFI inlet line 182 is also in fluid communication with the mixing junction 185 such that the buffer inlet line 181 and WFI inlet line 182 are in fluid communication with each other via the mixing junction 185. In the illustrated embodiment, the hybrid junction 185 is in the form of a "T" piece.

In an embodiment, buffer inlet line 181 includes at least one buffer inlet port 201-06 in fluid communication therewith. In the embodiment shown, manifold 23 includes six buffer inlet ports 201-06 in fluid communication with buffer inlet line 181. Control valves 151-56 are interposed between each of the buffer inlet ports 201-06, respectively, and the buffer inlet line 181 to selectively control the flow of concentrated buffer into the buffer inlet line 181 through each of the buffer inlet ports 201-06.

Buffer drain junction 186 is in fluid communication with and is interposed between buffer inlet line 181 and WFI inlet line 182. The buffer inlet line 181 extends between the buffer discharge fitting 186 and the mixing fitting 185.

Control valves

157, 158 are disposed upstream of buffer discharge junction 186 in WFI inlet line 182 and buffer inlet line 181, respectively. The buffer discharge control valve 158 can be selectively operated to allow the buffer inlet line 181 to be in fluid communication (via WFI inlet line 182) with the waste line 184 for buffer discharge operations. The WFI inlet control valve 157 may be selectively operated to control the flow of WFI through the WFI inlet line 182.

The WFI inlet line 182 includes a water port 207 in fluid communication therewith. In an embodiment, WFI inlet port 207 may be fluidly connected to a suitable WFI source. In an embodiment, the WFI source may comprise a WFI tank. In an embodiment, the WFI is produced using an on-site WFI generation system that uses at least one of multi-effect distillation and vapor compression.

WFI inlet line 182 extends between water port 207 and mixing junction 185. The WFI inlet line 182 is in fluid communication with the waste line 184 via a WFI discharge joint 187. A WFI drain fitting 187 is disposed between the water inlet port 207 and the mixing fitting 185. The WFI discharge joint 187 is in fluid communication with both the WFI inlet line 182 and the waste line 184 such that the WFI inlet line 182 is in fluid communication with the waste line 184 via the WFI discharge joint 187. A first waste control valve 159 is deployed in the waste line 184 downstream of the WFI discharge joint 187 to selectively prevent fluid flow from the WFI inlet line 182 to the waste line 184.

The discharge line 183 is in fluid communication with both the buffer inlet line 181 and the WFI inlet line 182 via a mixing junction 185. The drain line 183 is in fluid communication with the waste line 184 via a drain discharge fitting 188. The discharge line 183 extends between the mixing junction 185 and the discharge junction 188. A discharge drain fitting 188 is in fluid communication with the discharge line 183 and the waste line 184. Second and third

waste control valves

160, 167 are disposed upstream and downstream, respectively, of a discharge connection 188 in the waste line 184. Buffer inlet line 181 is in fluid communication with waste line 184 via buffer discharge junction 186, WFI line 182, and WFI discharge junction 187.

In an embodiment, drain line 183 includes at least one buffer drain port 211-16 in fluid communication therewith. In the illustrated embodiment, manifold 23 includes six buffer drain ports 211-216 in fluid communication with drain line 183. In an embodiment, the number of outlet ports 211-216 corresponds to the number of buffer inlet ports 201-206. Control valves 161-166 are interposed between each of the buffer drain ports 211-16 and the drain line 183 to selectively control the flow of the diluted buffer solution out of the manifold through each of the buffer drain ports 211-216 to the diluted

buffer tower

28, 29.

In the embodiment shown, the drain line is also in fluid communication with an integrity test line 190. In embodiments, the integrity test line 190 may be used to perform other suitable sampling and testing of the generated buffer solution, as will be appreciated by those skilled in the art. In an embodiment, compressed air may be introduced into the manifold 23 via the integrity test line 190 for a pressure decay test, which will give an indication of whether the manifold 23 is intact.

The waste line 184 is in fluid communication with the WFI inlet line 182 via a WFI discharge joint 187 and in fluid communication with the discharge line 183 via a discharge joint 188. Waste line 184 is in fluid communication with buffer inlet 181 line via buffer drain junction 186, WFI line 182, and WFI drain junction 187. The waste outlet port 217 is in fluid communication with the waste line 184. In an embodiment, fluid may be discharged from the waste line 184 through the waste outlet port 217 into a suitable tank or facility drain.

In the illustrated embodiment, the waste line 184 extends between the WFI drain fitting 187 and the waste outlet port 217. The waste line 184 has three

control valves

159, 160, 167 associated therewith to selectively block the waste line 184. The first and second

waste control valves

159, 160 may be used to selectively block the portion of the waste line 184 that fluidly connects the buffer inlet line 181 and the WFI inlet line 182 to the waste outlet port 217. The third waste control valve 167 can be used to selectively block the portion of the waste line 184 downstream of the discharge drain fitting 188. In an embodiment, each of the ports 201-207, 211-217 has a respective one of a plurality of control valves 151-157, 161-167 in operable relationship therewith to selectively block a respective one of the buffer inlet ports 201-206, the WFI inlet port 207, the buffer drain ports 211-216 and the waste outlet 217 via the control unit 100.

In embodiments, control valves 151-167 may be any type of control valve suitable for selectively controlling the flow of fluid through manifold 23, as discussed further below. For example, in an embodiment, the control valves 151-167 include pinch valves configured to selectively block an orifice within each flexible line at a point of contact between the pinch valve and the tubing. The control valves 151-67 are operatively arranged with the control unit 100 such that the control unit 100 can selectively operate the control valves 151-67. In the illustrated embodiment, the control unit 100 is configured to operate each of the control valves 151-167 independently.

In the embodiment shown, manifold 23 includes a buffer pump head 191 and a WFI pump head 192. A buffer pump head 191 is disposed in the buffer inlet line 181 and is configured to be operably disposed with the buffer pump body 145 in the cabinet 139 of the inline dilution slide 30 to selectively create fluid displacement within the buffer inlet line 181 by operation of the buffer pump body 145. The buffer pump head 191 is configured to be operably arranged with the buffer pump body 145 in the cabinet 139 of the dilution slide 30 such that the buffer pump can be operated to draw at least one selected concentrated buffer solution from the concentrated

buffer rack tower

22, 26, 27 through the buffer inlet line 181.

A WFI pump head 192 is deployed in WFI inlet line 182 and is configured to be operably disposed with the WFI pump 147 in cabinet 139 of online dilution skid 30 to selectively generate fluid displacement within WFI inlet line 182 by operating the WFI pump 147. The WFI pump head 192 is configured to be operably disposed with the WFI pump body 147 in the cabinet 139 of the dilution skid 30 such that the WFI pump can be operated to pump a supply of WFI from a WFI source through the WFI inlet line 182. In an embodiment, control unit 100 is configured to control at least one of the pump speed and the volumetric displacement of at least one of buffer pump 145 and WFI pump 147 to adjust the volumetric ratio of buffer solution flowing through buffer inlet line 181 to the amount of WFI flowing through WFI inlet line 182 and mixed together in discharge line 183.

In an embodiment, manifold 23 includes at least one buffer

characteristic sensor

171, 173 disposed in discharge line 183, the buffer

characteristic sensor

171, 173 configured to detect a value of a buffer characteristic of fluid in discharge line 183 and generate a buffer characteristic signal indicative of the value of the sensed buffer characteristic. In the illustrated embodiment, manifold 23 includes two buffer

characteristic sensors

171, 173 disposed in discharge line 183, i.e., conductivity sensor 171 and pH sensor 173, which are configured to transmit conductivity signals and pH signals, respectively, to control unit 100.

In an embodiment, at least one operation sensor 172 may also be provided in the discharge line 183. The control unit 100 may be configured to use the signals received from the operation sensor 172 to determine whether the manifold 23 is operating within a desired operating range for a desired fluid characteristic. In the illustrated embodiment, the manifold 23 includes a pressure sensor 172 disposed in the discharge line 183, the pressure sensor 172 configured to transmit a pressure signal to the control unit 100. The control unit 100 may be configured to use the pressure signal to determine whether the manifold 23 is operating within a desired operating pressure range (e.g., such as within a safe operating pressure range).

In an embodiment, and as shown in fig. 7, at least one buffer characteristic sensor 174 is associated with the waste line 184 and configured to sense a value of a buffer characteristic of the buffer solution in the waste line 184 and transmit a buffer characteristic signal indicative of the sensed value of the buffer characteristic to the control unit 100. In an embodiment, the control unit 100 may use the buffer characteristic signal received from the waste line 184 to control the operation of the buffer management system 20.

In an embodiment, the buffer characteristic sensor 174 in the waste line 184 may be any suitable sensor, such as a conductivity sensor. In an embodiment, the discharge line 183 and the waste line 184 may have at least one

sensor

171, 174 of the same type associated therewith. For example, in an embodiment, the first buffer characteristic sensor 171 in the discharge line 183 and the buffer characteristic sensor 174 in the waste line 184 both comprise conductivity sensors.

In the illustrated embodiment, a second conductivity sensor 174 disposed in the waste line 184 is configured to transmit a second conductivity signal to the control unit 100. In an embodiment, the buffer management program may be configured to use the second conductivity signal to identify the liquid passing through the waste line 184 and/or to determine whether the buffer solution passing through the waste line 184 is within a predetermined tolerance range of a given specification of a desired buffer. In an embodiment, the control unit 100 is configured to use the second conductivity signal from the second conductivity sensor 174 to assess whether the conductivity of WFI is within a predetermined range, such that it is suitable for use in preparing the desired buffer solution. In an embodiment, the control unit 100 is configured to determine whether the liquid passing through the waste line is within a predetermined tolerance range of a given specification of a desired buffer based on the buffer characteristic signal, and to block the waste line 184 (and open one of the buffer drain ports 211-216) via the third waste control valve 167 when the fluid in the waste line is within the predetermined tolerance range.

In an embodiment, the control unit 100 is configured to automatically control the operation of the buffer management system 20 to prepare a buffer within a predetermined tolerance of a given specification. In an embodiment, the control unit 100 is configured to automatically control operation of at least one of the buffer pump and the WFI pump to produce a desired buffer solution in response to information received via the at least one sensor feedback loop. In an embodiment, the control unit 100 is configured to control the pump speed/volumetric displacement of at least one of the buffer pump and the WFI pump to adjust the ratio of concentrated buffer to WFI mixed together in the discharge line 183 to achieve a desired buffer formulation.

Referring to fig. 7, in an embodiment, the processor 107 is programmed with a buffer management program stored on the computer readable medium 108. In an embodiment, the buffer management program includes an identification module configured to automatically identify the buffer passing through the manifold 23. In an embodiment, the identification module is configured to automatically identify the concentrated buffer solution entering the manifold 23 via one of the buffer inlet ports 201-206 and passing through the manifold 23 based on at least one buffer characteristic signal transmitted from the at least one buffer

characteristic sensor

171, 173, 174. In the illustrated embodiment, the processor 107 is in electrical communication with each buffer

characteristic sensor

171, 173, 174 of the manifold 23 to receive a respective buffer characteristic signal therefrom.

In an embodiment, the data storage device 109 includes buffer solution characterization data for a plurality of different buffer formulations. The identification module of the buffer management program may be configured to identify the concentrated buffer passing through the manifold 23 by analyzing at least one buffer characteristic signal received from at least one buffer

characteristic sensor

171, 173, 174 to determine which buffer formulation most closely matches the buffer characteristic signal(s) received from the buffer

characteristic sensor

171, 173, 174.

In an embodiment, the buffer formulations stored in the data storage device 109 each include buffer solution characteristic data for at least two different buffer characteristics (such as, for example, conductivity and pH). In an embodiment, the identification module of the buffer management program is configured to identify the concentrated buffer solution passing through the manifold based on the values of the buffer characteristic signals from two different buffer characteristic sensors 171-74 (such as the pH sensor 173 and at least one of the buffer conductivity sensors 171, 174).

In embodiments, the buffer formulation may be loaded onto the storage device 109 using any suitable technique, as will be appreciated by those skilled in the art. For example, in an embodiment, the control unit 100 includes a Human Machine Interface (HMI) 110 configured to receive at least one operator input in the form of a buffer formulation. In an embodiment, the buffer management program includes a formula manager module configured to store buffer solution characterization dates for at least one buffer formula in the data storage device for use by the identification module. The recipe manager module may be configured to store in a logical manner for the processor 107 to use at least one buffer recipe input into the storage device 109 via the HMI 110.

In an embodiment, the identification module of the buffer management program is configured to draw the concentrated buffer solutions sequentially through each of the buffer inlet ports 201-06 to identify which of the set of concentrated buffer solutions from the concentrated buffer rack towers 22, 26, 27 is connected to which of the buffer inlet ports 201-206 based on the buffer characteristic signal(s) received from the buffer characteristic sensor(s) 171, 173, 174. The identification module of the buffer management program may be configured to store the identity of the concentrated buffer solution fluidly connected to each of the buffer inlet ports 201-206 in the data storage device 109.

Embodiments of the buffer management system 20 constructed according to the principles of the present disclosure may reduce the space required in the buffer preparation chamber relative to conventional methods. In applications requiring the use of relatively large amounts of full strength buffer (e.g., 2000L), only 200L of tote bags (based on 10-fold dilution) can be used. In applications where the total volume of buffer is 20000L, 2000L of concentrated buffer solution (based on 10-fold dilution) can be used with a buffer management system constructed in accordance with the principles of the present disclosure.

In other embodiments of buffer management systems constructed in accordance with the principles of the present disclosure, the in-line buffer dilution system configuration may take alternative forms. For example, in an embodiment, the workstation may be replaced with a tote bag. In other embodiments, the buffer management system may be scaled for larger buffer volumes or reduced for laboratory use. In an embodiment, the manifold assembly may be constructed of a rigid plastic construction. In an embodiment, a management system constructed in accordance with the principles of the present disclosure may be used to process liquids other than buffer solutions to meet the requirements of another application.

In an embodiment of a method of using a buffer management system 20 consistent with the principles of the present disclosure, a buffer management system 20 constructed in accordance with the principles of the present disclosure is used to continuously produce a desired buffer solution, as discussed herein. In embodiments, methods of using buffer management systems consistent with the principles of the present disclosure may be used with any embodiment of a buffer management system 20 according to the principles discussed herein, which may include an embodiment of an inline dilution skid 30 with a single-use manifold 23 according to the principles of the present disclosure.

In one embodiment, a method of using the buffer management system 20 includes drawing a quantity of buffer concentrate and a quantity of water for injection (WFI) to the in-line dilution skid 30. The amount of buffer concentrate and the amount of WFI are mixed at an in-line dilution skid to form a diluted buffer solution.

The buffer characteristics of the diluted buffer solution are sensed at the online dilution skid 30. A buffer characteristic signal indicative of the value of the sensed buffer characteristic is transmitted to the control unit 100. The control unit 100 is used to determine whether the diluted buffer solution is within a predetermined tolerance range for the selected buffer formulation based on the buffer characteristic signal. Once the control unit determines that the diluted buffer solution is within a predetermined tolerance range, the diluted buffer solution is discharged from the inline dilution skid 30 to the biocontainer 55.

In an embodiment, the method further comprises discharging the diluted buffer solution from the inline dilution skid 30 through a waste line 184 when the control unit 100 determines that the diluted buffer solution is outside of the predetermined tolerance range. The controller 100 is used to adjust at least one of a buffer pump drawing an amount of buffer concentrate to the in-line dilution skid 30 and a WFI pump drawing an amount of WFI to the in-line dilution skid 30 based on the buffer characteristic signal.

In an embodiment, an embodiment of a buffer management system 20 constructed in accordance with the principles of the present disclosure may be used to draw at least one buffer concentrate stored in a concentrated

buffer rack tower

22, 26, 27 through a conduit to an online diluent skid 30 and mix the concentrated buffer with an amount of WFI (water for injection) in a ratio that may be varied by adjusting at least one of the buffer pump and the WFI pump through the mixing T-piece 185. Once mixed, the diluted buffer solution passes through a first conductivity sensor 171 and then a pH sensor 173. The buffer management program of the control unit 100 may be operable to determine whether the diluted buffer solution passing through the discharge line 183 is within a predetermined tolerance of the selected buffer formulation based on at least one of the first conductivity signal and the pH signal. The diluted buffer solution is transferred to the waste line 184 until the correct specifications are reached. The control unit 100 is configured to automatically control the manifold 23 to produce a desired diluted buffer formulation and send the diluted buffer solution to a desired surge receptacle bag 55 of the diluted

buffer rack tower

28, 29 by control of the control valves 201-217 of the dilution skid 30 and control of at least one of the buffer pumps and WFI pumps based on signals received from the

feedback sensors

171, 173, 174.

A second conductivity signal from the second conductivity sensor 174 in the waste line 184 may be sent to the control unit 100 and used by the buffer management program to determine whether the diluted buffer solution passing through the waste line 184 is within the specifications of the selected buffer formulation. Because the mixing of the concentrated buffer solution and WFI may continue as the combined liquids pass through the waste line 184, monitoring the second conductivity signal to determine whether the diluted buffer solution is within the specifications of the desired formulation helps to reduce the amount of solution transferred to the waste line 184.

Once the control unit 100 determines that the diluted buffer solution produced within the manifold 23 is within the specifications of the desired buffer formulation, the control unit 100 may operate the manifold 23 to direct the diluted buffer solution to a selected one of the surge biocontainers of the diluted

buffer tower

28, 29. The diluted buffer solution stored in the selected surge biocontainer is ready to be sent to an operational process (such as TFF or chromatography, for example).

In an embodiment of a method of using the buffer management system 20, following the principles of the present disclosure, a buffer management system 20 constructed according to the principles of the present disclosure is used to automatically identify the placement of buffers in a bioprocessing application. In embodiments, the method of performing a buffer identification operation using a buffer management system according to the principles of the present disclosure may be used with any embodiment of the buffer management system 20 according to the principles discussed herein, which may include an embodiment of an inline dilution skid 30 with a single use manifold 23 according to the principles of the present disclosure.

In one embodiment, a method of using a buffer management system includes drawing one of a set of amounts of concentrated buffer solution into a first buffer inlet port of a plurality of buffer inlet ports of a manifold. The buffer characteristics of the concentrated buffer solution are sensed in the manifold. A buffer characteristic signal indicative of the value of the sensed buffer characteristic is transmitted to the control unit. The control unit is used to identify the concentrated buffer solution entering the manifold via the first buffer inlet port based on the buffer characteristic signal.

In an embodiment, buffer solution characterization data for a plurality of buffer formulations may be loaded into the data storage device. The control unit may be configured to identify the concentrated buffer solution passing through the manifold by analyzing the buffer characteristic signal to determine one of the buffer formulations in the storage device that is closest to the buffer characteristic signal. In at least some of these embodiments, a second buffer characteristic of the concentrated buffer solution that is different from the first buffer characteristic may be sensed in the manifold. A second buffer characteristic signal indicative of the value of the sensed second buffer characteristic may be transmitted to the control unit. The control unit may be configured to identify a concentrated buffer solution entering the manifold via the first buffer inlet port based on the first buffer characteristic signal and the second buffer characteristic signal. In at least some of those embodiments, the first buffer characteristic and the second buffer characteristic comprise conductivity and pH, respectively.

Embodiments of methods of using buffer management systems consistent with principles of the present disclosure may include sequentially drawing a respective one of a set of quantities of concentrated buffer solution into each of a plurality of buffer inlet ports of a manifold. The buffer characteristics of a respective one of the concentrated buffer solutions may be sequentially sensed in the manifold. A buffer characteristic signal indicative of a value of a respective sensed buffer characteristic of a respective one of the set of concentrated buffer solutions may be sequentially transmitted to the control unit. The control unit may be sequentially used to identify a respective one of a set of concentrated buffer solutions entering the manifold via each of a plurality of buffer inlet ports of the manifold based on the buffer characteristic signal. The identity of the concentrated buffer solution fluidically connected to each of the buffer inlet ports may be stored in the data storage device.

Embodiments of methods of using a buffer management system consistent with principles of the present disclosure may include draining a volume of liquid from a first buffer drain port of a plurality of buffer drain ports of a manifold into one of a plurality of biocontainers. The plurality of buffer fluid outlet ports are in fluid communication with different ones of the plurality of biological vessels, respectively. The amount of material stored within each of the plurality of biocontainers may be separately sensed. A fill level signal indicative of a value of the amount of material sensed within each of the plurality of biocontainers may be transmitted to the control unit separately. The control unit is used to identify the biocontainer with which the first buffer outlet port is in fluid communication based on the change in the fill level signal therefrom.

In an embodiment, the fluid is sequentially discharged through each of the buffer discharge ports. The control unit is in turn used to identify the biocontainers with which each of the buffer drain ports is in fluid communication based on the variation of the filling level signal therefrom. The identity of the biocontainer fluidly connected to each of the buffer fluid outlet ports is stored in the data storage device.

Embodiments of methods of using buffer management systems consistent with the principles of the present disclosure may include sequentially draining an amount of liquid from each of the biological receptacles into a respective one of a plurality of cell inlet ports of a biological processing cell. The plurality of biological containers are each in fluid communication with a different one of the unit inlet ports of the biological treatment unit. The control unit is in turn used to identify the biocontainers with which each of the unit inlet ports is in fluid communication based on the variation of the filling level signal therefrom.

Referring to fig. 8-11, a first biocontainer surge bag filling sequence is shown. In an embodiment, each surge bag fill sequence includes flushing manifold 23, diverting buffer solution to waste line 184 until control unit 100 determines that the buffer solution produced is within a predetermined tolerance of a given diluted buffer formulation, and filling a selected one of the biocontainer surge bags of diluted buffer rack towers 28, 29 to a predetermined volume. In the illustrated embodiment, the initial surge bag fill sequence includes flushing the manifold 23, priming the WFI flow through the manifold 23, diverting the buffer solution to the waste line 184 until the control unit 100 determines that the buffer solution produced is within a predetermined tolerance of a given diluted buffer formulation, and filling a selected one of the biological container surge bags of the diluted buffer rack towers 28, 29 to a predetermined volume.

Referring to fig. 8, the manifold 23 is in the flush position. A rinse step is performed to remove any trace of buffer solution or any other impurities in the manifold 23 to initiate each fill sequence. In the flush position, control unit 100 of dilution slide 30 has controlled control valves 151-167 such that the concentrated buffer of the concentrated buffer rack tower and the biocontainer assembly of diluted buffer rack towers 22, 26, 27 are all fluidly isolated from manifold 23. The buffer inlet line 181, WFI inlet line 182, discharge line 183, and waste line 184 are all in fluid communication with a WFI source via WFI inlet port 207, such that WFI can flow through these

lines

181, 182, 183, 184 and out waste outlet port 217. In this arrangement, when the manifold 23 is in the flush position, multiple flow paths through the manifold are established from the WFI inlet port 207 to the waste outlet port 217. In the illustrated embodiment, the control unit 100 has operated the buffer inlet port control valves 151-156 and the buffer drain control valves 161-66 to block the respective buffer inlet ports 201-206 and drain ports 211-216.

In an embodiment, the rinsing step may be performed for a predetermined period of time. In an embodiment, the rinsing step may be performed until the buffer management program of the control unit 100 determines that the second conductivity signal from the second conductivity sensor 174 meets predetermined specifications.

Referring to fig. 9, the manifold 23 is in the WFI priming position. Since the demand for WFI in a typical buffer formulation can be between five to twenty times the amount of concentrated buffer solution mixed with WFI, in the manifold embodiment, WFI pump 192 is larger than buffer pump 191. Proportionally, the pumping capacity of WFI is greater than the pumping capacity of the buffer concentrate(s). A priming step may be included to bring the WFI flow through the manifold 23 to steady state before introducing the desired concentrated buffer solution into the manifold 23 to mix with the WFI.

In the WFI pre-fill position, the control unit 100 of the dilution slide has controlled the control valves such that both the concentrated buffer of the concentrated buffer rack tower and the biocontainer assembly of the diluted buffer rack tower are fluidly isolated from the manifold. Buffer inlet line 181 is fluidly isolated from WFI inlet line 182, discharge line 183, and waste line 184. The WFI inlet 182, drain line 183, and waste line 184 are all in fluid communication with a WFI source, such that WFI can flow through these

lines

182, 183, 184 into the WFI inlet 207 and out the waste outlet port 217. The control unit 100 has been operated to open the WFI inlet control valve 157 and the third waste control valve 167. In this arrangement, when the manifold 23 is in the priming position, a flow path is established through the manifold 23 from WFI inlet port 207 to waste outlet port 217 via WFI inlet line 182, drain line 183 and waste line 184.

Referring to fig. 10, the manifold 23 is in a first buffer stabilization position. The manifold 23 is maintained in the first buffer stable position such that the initially generated diluted buffer is transferred to the waste line 184 until the control unit 100 determines that the generated buffer solution is within a predetermined tolerance of a given diluted first buffer formulation.

In the first buffer steady position, the control unit 100 of the dilution skid has controlled the control valves 151-156 such that the first buffer inlet port 201 is in fluid communication with the buffer inlet line 181 and the other five buffer inlet ports 202-206 are in fluid isolation from the manifold 23. The control unit 100 has opened the WFI inlet control valve 157 such that the WFI inlet port is in fluid communication with the WFI inlet line 182 to allow WFI flow into it. Buffer drain ports 211-216 are fluidly isolated from drain line 183 so that the biocontainer assemblies of diluted buffer rack towers 28, 29 are all fluidly isolated from manifold 23. The WFI inlet line 182 and buffer inlet line 181 are in fluid communication with a discharge line 183, which discharge line 183 in turn is in fluid communication with a waste line 184, such that the combined first buffer concentrate and WFI flowing through the buffer inlet line 181 and WFI inlet line 182, respectively, can flow through the discharge line 183 and waste line 184, exiting the waste outlet port 217. In this arrangement, when the manifold 23 is in the first buffer stable position, multiple flow paths are established through the manifold 23, i.e., one flow path from the WFI inlet 207 to the waste outlet 217, and one flow path from the WFI inlet port 207 to the waste outlet port 217 and another flow path from the first buffer inlet port 201 to the waste outlet port 217.

In an embodiment, the manifold 23 is maintained in the first buffer stable position until the control unit 100 determines that the diluted buffer solution produced in the manifold 23 is within the predetermined specifications of the first buffer formulation. The control unit 100 may use the buffer data signals generated by at least one of the first conductivity sensor 171, the pH sensor 173, and the second conductivity sensor 174 to determine whether the diluted buffer solution produced in the manifold 23 is within the specifications of the desired first buffer formulation. In an embodiment, control unit 100 may be configured to adjust at least one of the flow rate of buffer pump 191 and the flow rate of WFI pump 192 to adjust the ratio of buffer concentrate to WFI mixed together in manifold 23 when the diluted buffer solution produced in manifold 23 is not within the specifications of the first diluted buffer formulation. The control unit 100 may be configured to use the sensor feedback loop(s) to adjust the operation of the buffer management system 20 until it is determined that the diluted buffer solution produced in the manifold 23 is within the specifications of the desired first buffer formulation.

In the first buffer stable position, the diluted buffer solution sent through the waste line 184 passes through the second conductivity sensor 174 positioned near the waste outlet port 217. Because the combined flow of first buffer concentrate and WFI continues to mix in the discharge line 183 between the first conductivity sensor 171 and the second conductivity sensor 174, the second conductivity signal can be used to help detect more quickly when the diluted buffer solution has achieved the specifications of the desired first diluted buffer formulation, thereby reducing the amount of viable buffer solution sent to waste.

Referring to fig. 11, the manifold 23 is in a first buffer fill position. The manifold 23 is maintained in the first buffer fill position so that diluted buffer solution within the specifications of the desired first diluted buffer formulation is delivered to the designated surge bag 55' of the diluted

buffer rack tower

28, 29 of the first diluted buffer formulation.

In the first buffer fill position, the control unit 100 of the dilution skid 30 has controlled the control valves 151-56 such that the first buffer inlet port 201 is in fluid communication with the buffer inlet line 181, while the other five buffer inlet ports 202-206 are in fluid isolation from the manifold 23. The first buffer drain port 211 is in fluid communication with the drain line 183 of the manifold 23, and the other buffer drain ports 212-216 are fluidly isolated from the manifold 23. The first buffer drain port 211 is in fluid communication with a biocontainer bag 55 'of the first dilute buffer rack tower 28, which biocontainer bag 55' is designated to receive a buffer solution made according to the first dilute buffer formulation. The buffer inlet line 181 and WFI inlet line 182 are in fluid communication with the discharge line 183, which in turn is in fluid communication with the first buffer discharge port 211, such that the combined first buffer concentrate and WFI flowing through the buffer inlet line 181 and WFI inlet line 182, respectively, can flow through the discharge line 183 and out of the first buffer discharge port 211. The waste line 184 is fluidly isolated from the exhaust line 183. In this arrangement, when the manifold 23 is in the first buffer fill position, multiple flow paths are established through the manifold 23, i.e., one flow path from the WFI inlet port 207 to the first buffer drain port 211 and another flow path from the first buffer inlet port 201 to the first buffer drain port 211, such that the first buffer drain port 211 receives the diluted buffer solution mixed according to the first diluted buffer formulation.

In the illustrated embodiment, in the first buffer fill position, the first buffer drain port 211 is in fluid communication via the first buffer drain port 211 with the diluted buffer rack tower's biocontainer bag 55' designated for receiving a buffer solution made according to the first diluted buffer formulation. It will be understood that in other embodiments, another buffer drain port (e.g., such as third buffer drain port 213) may be fluidly connected to the designated biocontainer bag to receive the first diluted buffer formulation. In this arrangement, when the manifold is in the first buffer fill position, a flow path is established through the manifold from the first buffer inlet port to the third buffer outlet port.

The manifold 23 may be maintained in the first buffer fill position to fill the designated surge bag 55 'with the first dilute buffer solution until the control unit 100 of the dilution skid 30 receives a first fill level signal from the first dilute buffer rack tower 28 indicating that the predetermined maximum fill amount of the first buffer solution has been stored in the designated surge bag 55'. Once the control unit 100 has received a fill level signal indicating that the designated surge bag 55' has the desired maximum amount of the first buffer solution, the control unit 100 may be operated to discontinue production of the first buffer solution.

In an embodiment, the control unit 100 may be configured to maintain the volume of the first buffer solution in the surge bag 55' at a desired minimum fill level. In an embodiment, when the first fill level signal from the first biocontainer bag 55 'indicates that the level of the first buffer solution in the first biocontainer bag 55' is below a predetermined level, the control unit 100 may be configured to run a first buffer fill sequence to bring the level of the first buffer solution back above a predetermined operating level. In an embodiment, the operating level may be different from the maximum filling level. In an embodiment, as part of a bioprocessing application, each biocontainer assembly may be configured to monitor the level of liquid within each biocontainer bag 55. In an embodiment, the buffer management system 20 may be configured to use the fill level signals received from each capacitive level sensor of the biocontainer assembly to monitor how the volume of liquid stored within each bag 55 changes, thereby obtaining real-time feedback. The monitoring of the fill level signal can be used in various modes of operation in the buffer management system 20. For example, in an embodiment, the fill level signal can be monitored to maintain the volume of buffer solution in each respective surge bag 55' to a desired minimum fill level.

Referring to fig. 12 and 13, a second biocontainer surge bag filling sequence is shown. In an embodiment, different buffer solutions are used for a given bioprocessing application. In embodiments, the buffer management system 20 is configured to generate different diluted buffer solution formulations for use in such bioprocessing applications. In an embodiment, the buffer management system 20 may be used to sequentially produce a plurality of diluted buffer solutions. The dilution skid 30 may be configured to perform a wash step each time the production of diluted buffer solution is switched from one buffer formulation to another. In an embodiment, the buffer management system 20 begins each fill sequence with a flush cycle, as shown in fig. 8. In an embodiment, the second surge bag fill sequence includes flushing manifold 23, transferring the second buffer solution to waste line 184 until control unit 100 determines that the resulting buffer solution is within a predetermined tolerance of the given second diluted buffer formulation, and filling a selected one of the biological container surge bags of diluted buffer rack towers 28, 29 to a predetermined volume.

In an embodiment, when system 20 first draws any liquid in manifold 23 (until this time the manifold is dry), a priming is included in the initial buffer fill sequence. When the system 20 switches between buffers, i.e., dilutes one buffer and prepares to move to a second buffer, it is sufficient to perform a WFI flush alone between the two steps (no priming is required because the manifold is already filled with liquid from the previous step).

Referring to fig. 12, the manifold 23 is in a second buffer stabilization position. The manifold 23 is maintained in the second buffer stable position such that the initially generated diluted buffer solution is transferred to the waste line 184 until the control unit 100 determines that the generated buffer solution is within a predetermined tolerance of a given second diluted buffer formulation. In an embodiment, the buffer formulation of the second dilution is different from the buffer formulation of the first dilution.

In the second buffer stable position, the control unit 100 of the dilution skid 30 has controlled the control valves 151-156 such that the second buffer inlet port 202 is in fluid communication with the buffer inlet line 181 and the first and second third through sixth buffer inlet ports 201, 203-206 are fluidly isolated from the manifold 23. The control unit 100 has opened the WFI inlet control valve 157 such that the WFI inlet port 207 is in fluid communication with the WFI inlet line 182 to allow WFI flow to enter therein. The buffer drain ports 211-216 are fluidly isolated from the drain line 183 such that the biocontainer assemblies of the diluted buffer rack towers 28, 29 are all fluidly isolated from the manifold 23. The buffer inlet line 181 and WFI inlet line 182 are in fluid communication with the discharge line 183, which in turn is in fluid communication with the waste line 184, such that the combined second buffer concentrate and WFI flowing through the buffer inlet line 181 and WFI inlet line 182, respectively, can flow through the discharge line 183 and waste line 184, exiting the waste outlet port 217. In this arrangement, when the manifold 23 is in the second buffer stabilization position, multiple flow paths are established through the manifold 23, i.e., one flow path from the WFI inlet port 207 to the waste outlet port 217 and another flow path from the second buffer inlet port 202 to the waste outlet port 217.

In an embodiment, the manifold 23 is maintained in the second buffer stable position until the control unit 100 determines that the diluted buffer solution produced in the manifold 23 is within the predetermined specifications of the second buffer formulation. The control unit 100 may be configured to control the operation of the manifold 23 in the manner described above in connection with the first buffer steady position. The control unit 100 may use the buffer data signals generated by at least one of the first conductivity sensor 171, the pH sensor 173, and the second conductivity sensor 174 to determine whether the diluted buffer solution produced in the manifold 23 is within the specifications of the desired second diluted buffer formulation. In an embodiment, control unit 100 may be configured to adjust at least one of the flow rate of buffer pump 191 and the flow rate of WFI pump 192 to adjust the ratio of buffer concentrate to WFI mixed together in the manifold in response to determining that the diluted buffer solution produced in manifold 23 is not within the specifications of the second diluted buffer formulation. The control unit 100 may use the sensor feedback loop(s) to adjust the operation of the buffer management system until it is determined that the diluted buffer solution produced in the manifold 23 is within the specifications of the desired second diluted buffer formulation.

Referring to fig. 13, the manifold 23 is in the second buffer fill position. The manifold 23 is maintained in the second buffer fill position to deliver diluted buffer within the specifications of the desired second diluted buffer formulation to the designated surge bags of the diluted buffer rack towers 28, 29 for the second diluted buffer formulation.

In the second buffer fill position, the control unit 100 of the dilution skid 30 controls the control valves 151-156 such that the second buffer inlet port 202 is in fluid communication with the buffer inlet line 181 and the first and third through sixth buffer inlets 201, 203-206 are fluidly isolated from the manifold 23. The second buffer drain port 212 is in fluid communication with the drain line of the manifold, and the first and third through sixth buffer drain ports 211, 213-216 are fluidly isolated from the manifold 23. The second buffer drain port 212 is in fluid communication with the biocontainer bag of the diluted

buffer rack tower

28, 29, the diluted

buffer rack tower

28, 29 being designated for receiving a buffer solution made according to the second diluted buffer formulation. The buffer inlet line 181 and WFI inlet line 182 are in fluid communication with the discharge line 183, which in turn is in fluid communication with the second buffer discharge port 212, such that the combined second buffer concentrate and WFI flowing through the buffer inlet line 181 and WFI inlet line 182, respectively, can flow through the discharge line 183 and out of the second buffer discharge port 212. The waste line 184 is fluidly isolated from the exhaust line 183. In this arrangement, when the manifold 23 is in the second buffer fill position, multiple flow paths through the manifold are established, i.e., one flow path from the WFI inlet port 207 to the second buffer drain port 212 and another flow path from the second buffer inlet port 202 to the second buffer drain port 212, such that the second buffer drain port 212 receives the diluted buffer solution mixed according to the second diluted buffer formulation.

In the illustrated embodiment, in the second buffer fill position, the second buffer drain port 212 is in fluid communication with the biocontainer bag of the diluted

buffer rack tower

28, 29 designated for receiving a buffer solution made according to the second diluted buffer formulation via the second buffer drain port 212. It will be understood that in other embodiments, another buffer drain port (e.g., such as the third buffer drain port 213) may be fluidly connected to a designated biocontainer bag for receiving the second diluted buffer formulation. In this arrangement, when the manifold 23 is in the second buffer filling position, a flow path is established through the manifold from the second buffer inlet port 202 to the third buffer outlet port 213.

The manifold 23 may be maintained in the second buffer fill position to fill the designated surge bag with the second diluted buffer solution until the control unit 100 receives a second fill level signal from the diluted buffer rack towers 28, 29 indicating that the predetermined maximum fill amount of the second buffer solution has been stored in the designated surge bag. Once the control unit 100 has received a second fill level signal indicating that the designated surge bag has the desired maximum amount of the second buffer solution, the control unit 100 may be operated to discontinue the generation of the second buffer solution. The operation of the dilution skid 30 with respect to the generation and maintenance of the second diluted buffer solution may be otherwise similar to that described with respect to the first diluted buffer solution.

In the embodiment shown, the manifold 23 comprises six buffer inlet ports 201-206 for up to six different buffer concentrates for generating buffer solutions of different diluted buffer formulations. The buffer fill sequence can be performed in a similar manner for the third through sixth concentrated buffer solutions with the third through sixth buffer inlet ports 203-206, respectively. In other embodiments, a different number of buffer inlet ports 201-206 may be provided.

Referring to fig. 14 and 15, a buffer concentrate discharge sequence is shown. In an embodiment, each buffer concentrate stored in the concentrated buffer rack towers 22, 26, 27 may be drained from the respective tote bags in a sequential manner. This operation may occur after completion of the desired bioprocessing application to facilitate preparation of the buffer management system 20 for another bioprocessing application using a new single-use manifold.

Referring to fig. 14, the manifold 23 is in a first concentrated buffer discharge position. The manifold 23 is maintained in the first concentrated buffer discharge position so that the first concentrated buffer solution stored in the concentrated buffer rack towers 22, 26, 27 can be discharged therefrom.

In the first concentrated buffer discharge position, the control unit 100 of the dilution skid 30 controls the control valves 151-156 such that the first buffer inlet port 201 is in fluid communication with the buffer inlet line 181, while the other five buffer inlet ports 202-06 are in fluid isolation from the manifold 23. The biocontainer assemblies of diluted

buffer tower

28, 29 are all fluidly isolated from manifold 23. The buffer inlet line 181 is in fluid communication with the discharge line 183, and the discharge line 183 is in turn in fluid communication with the waste line 184, such that the first buffer concentrate can flow from the concentrated buffer rack towers 22, 26, 27, through the first buffer inlet port 201, the buffer inlet line 181, the discharge line 183, and the waste line 184, and out through the waste outlet port 217. The WFI inlet line 182 is fluidly isolated from the buffer inlet line 181, the discharge line 183, and the waste line 184. In this arrangement, when the manifold 23 is in the first concentrated buffer discharge position, a flow path is established from the first buffer inlet port 201 through the manifold 23 to the waste outlet port 217.

The control unit 100 may be configured to operate the buffer pump 191 to perform a first concentrated buffer discharge sequence. In an embodiment, the control unit 100 may be configured to operate the first concentrated buffer discharge sequence by placing the manifold 23 in the first concentrated buffer discharge position and operating the buffer pump 191 for a predetermined period of time. In an embodiment, the buffer management system may comprise a suitable flow meter of the first concentrated buffer solution along the discharge path, which flow meter is arranged in communication with the control unit 100 to receive therefrom a signal indicative of the liquid flow through the flow path. In an embodiment, the control unit 100 may be configured to operate the buffer pump 191 to perform a first concentrated buffer discharge sequence until the flow signal indicates that the liquid flow along the discharge path is below a predetermined threshold.

Referring to fig. 15, the manifold 23 is in a second concentrated buffer discharge position. The manifold 23 is maintained at the second concentrated buffer discharge position so that the second concentrated buffer solution stored in the concentrated buffer rack tower can be discharged therefrom.

In the second concentrated buffer discharge position, the control unit of the dilution skid has controlled the control valves 151-156 such that the second buffer inlet port 202 is in fluid communication with the buffer inlet line 181 and the first and third through sixth buffer inlet ports 201, 203-206 are fluidly isolated from the manifold 23. The biocontainer assemblies 25 of the diluted buffer tower are all fluidly isolated from manifold 23. The buffer inlet line 181 is in fluid communication with the discharge line 183, and the discharge line 183 is in turn in fluid communication with the waste line 184, such that the second buffer concentrate can flow from the concentrated buffer rack tower, through the second buffer inlet port 202, the buffer inlet line 181, the discharge line 183, and the waste line 184, and out through the waste outlet port 217. WFI inlet line 182 is fluidly isolated from buffer inlet line 181, discharge line 183, and waste line 184. In this arrangement, when the manifold 23 is in the second concentrated buffer discharge position, a flow path is established from the second buffer inlet port 202 through the manifold 23 to the waste outlet port 217.

The control unit may be configured to perform the second concentrated buffer drain sequence in a manner similar to that described above in connection with the first concentrated drain sequence. The discharge sequence of the concentrated buffer solution may be performed in a similar manner for the third to sixth concentrated buffer solutions with the third to sixth buffer inlet ports 203-206, respectively.

Referring to fig. 16, the manifold 23 is in the system exhaust position. The manifold 23 is maintained in a system drain position so that liquid stored within the system can be drained therefrom.

In the system discharge position, the control unit 100 of the dilution skid 30 has controlled the control valves 151-156, 161-166 such that all buffer inlet ports 201-206 are in fluid communication with the buffer inlet line and the buffer discharge ports 211-1 are all in fluid communication with the discharge line 183. Buffer inlet line 181 is in fluid communication with WFI inlet line 182 via buffer discharge fitting 186, which buffer discharge fitting 186 is in turn in fluid communication with waste line 184. The discharge line 183 is in fluid communication with a waste line 184. In this arrangement, when the manifold 23 is in the system exhaust position, multiple flow paths are established from each buffer inlet port 201-06 through the manifold 23 to the waste outlet port 217 and from each buffer outlet port 211-16 through the manifold 23 to the waste outlet port 217. As such, with the system, liquid can be drained through the waste outlet port 217 by the action of gravity when the manifold 23 is in the system drain position. In embodiments, the manifold 23 may be placed in various suitable configurations and in various sequences to effectively discharge fluid from the manifold 23. Those skilled in the art will recognize that this can be accomplished by a variety of techniques that will be familiar to those skilled in the art.

In an embodiment, the control unit 100 is configured to place all control valves in an open position when the manifold 23 is in the system exhaust position. The system drain location may be used to assist in draining liquid from the manifold 23. With all control valves open, excess liquid in the manifold 23 may be allowed to flow to a drain point by the action of gravity. An air line 190 at the top of the manifold 23 may be opened to assist in displacing liquid from the manifold 23. The exhaust fluid within the manifold 23 may help facilitate the handling and disposal of the used manifold 23.

The control unit 100 may be configured to operate a system drain sequence. In an embodiment, the control unit 100 may be configured to operate the system drain sequence by placing the manifold 23 in the system drain position for a predetermined period of time. In an embodiment, the buffer management system may comprise a suitable flow meter along the discharge path near the waste outlet port 217, which is arranged in communication with the control unit 100 to receive therefrom a flow signal indicative of the liquid flow through the flow path. In an embodiment, the control unit 100 may be configured to maintain at least the manifold 23 in the system discharge position until the flow signal indicates that the liquid flow along the discharge path is below a predetermined threshold.

Referring to fig. 17, in an embodiment, the buffer management program stored in the computer readable medium 108 of the control unit 100 may include an identification module configured to automatically identify the buffer solution passing through the manifold 23. In an embodiment, the buffer management program may be configured to identify the flow path of a given buffer solution from the concentrated buffer rack towers 22, 26, 27 through the manifold 23 to the diluted buffer rack towers 27, 28, so the control unit 100 will know which buffers (concentrated buffer and diluted buffer) pass through which buffer inlet ports 201-06 and buffer outlet ports 211-216, respectively, of the manifold 23 of the dilution skid, and which biocontainers of the diluted buffer rack towers 27, 28 receive the respective buffer solution from the manifold 23. With this automatic identification function of the buffer management program in place, the operator does not need to follow a set connection pattern between the tote bags and manifold 23 of the concentrated buffer rack towers 22, 26, 27 or the biocontainers 29 and manifold 23 of the diluted buffer rack tower 28. Once the arrangement of buffer solutions in the buffer management system 20 is identified, the control unit 100 may transmit this information to the biological processing unit 24, so that the biological processing unit 24 may manipulate a particular line in the dilute buffer rack towers 28, 29 in order to draw a particular buffer solution thereto.

In an embodiment, a user may operate the control unit 100 to input buffer solution characteristic data for each buffer formulation selected for a given bioprocessing application in which the buffer management system is intended to be used. Table I below contains an example of such buffer characterization data for samples of six different buffer solutions, where the first three buffers are three different concentrated buffers and the last three buffers are the equivalents of their respective diluted forms (1 ×). In embodiments, the buffer characterization data may include information about each buffer solution relating to suitable characteristics familiar to those skilled in the art, such as, for example, pH, conductivity, and concentration factor. In an embodiment, the buffer solution characteristic data may be input to the data storage device 109 of the control unit 100 of the dilution skid 30 via a Human Machine Interface (HMI) 110 of the control unit 100.

In an embodiment, the HMI 110 may be located on the dilution skid 30. In other embodiments, HMI 110 may be part of a mobile application ("app") or otherwise located remotely from dilution skid 30 and communicate with control unit 100 via a wireless network. In an embodiment, the buffer management program is configured to store buffer solution characteristic data received through the HMI 110 in the data storage device 109 in a logical manner as part of a recipe manager module of the buffer management program to retrieve from time to time in the process of identifying buffer solutions in accordance with the principles of the present disclosure.

TABLE 1 characteristics of buffer solutions

Referring to fig. 17, in an embodiment of a process of identifying an arrangement of different buffer solutions in fluid communication with a plurality of buffer inlet ports 201-206 of a manifold 23 of a buffer management system 20 following the principles of the present disclosure, the control unit 100 may be used to sequentially place the manifold 23 in first through sixth buffer discharge positions to determine which buffer solution the manifold 23 has drawn through the first through sixth buffer inlet ports 201-06, respectively.

In fig. 17, a set of concentrated buffer containers 1-6 are connected to the first through sixth buffer inlet ports 201-206 in an unrelated manner unknown to the buffer management program (i.e., e.g., buffer container 3 is connected to the first buffer inlet port 201 of the manifold 23). The identification module of the buffer management program may be configured to sequentially place the manifold 23 at the first to sixth buffer discharge positions to systematically identify which of the set of concentrated buffers in the concentrated buffer rack tower is connected to which of the first to sixth buffer inlet ports 201-206.

In an embodiment, the buffer management program is configured to undergo the following sequence: the buffer inlet ports 201-206 are opened starting from the first buffer inlet port 201 and the first buffer discharge path is opened by placing the manifold 23 in a first buffer discharge position, as shown in fig. 17, wherein the first buffer inlet port 201 is in fluid communication with the waste outlet port 217. The control unit 100 may operate the buffer pump 191 to draw a supply of a third concentrated buffer from the bio-containers 3 of the concentrated buffer rack towers 22, 26, 27 (as this is the bio-container of the concentrated buffer rack tower in fluid communication with the first buffer inlet port 201) and deliver it through the manifold 23 and out the waste outlet port 217 of the waste line 184.

The first conductivity sensor 171 and the pH sensor 173 may transmit the first conductivity signal and the pH signal to the control unit 100. The identification module of the buffer management program may be configured to analyze at least one of the first conductivity signal and the pH signal to determine which of the different buffer formulations stored in the data storage device 109 most closely matches the buffer solution passing through the manifold 23. In an embodiment, the identification module may be configured to use the second conductivity signal from the second conductivity sensor 174 in addition to or instead of the first conductivity signal and the pH signal. In an embodiment, the buffer management program is configured to identify the concentrated buffer passing through the manifold 23 based on at least one of the values of conductivity and pH sensed by the

manifold sensors

171, 173, 174 and the buffer recipe stored in the control unit 100, which serves as a unique identifier for the buffer. In an embodiment, the buffer management program is configured to identify the concentrated buffer passing through the manifold 23 based on both the conductivity and pH values sensed by the

manifold sensors

171, 173, 174, serving as unique identifiers for the buffers, and the buffer recipe stored in the control unit 100. The identification module of the buffer management program is configured to store the identity of the buffer solution fluidly connected to the first buffer inlet port 201 in the data storage device 109 in a logical manner so that this information can be retrieved for later use by the buffer management program.

By the identification module sequentially placing the manifold 23 in the second to sixth buffer discharge positions, the above identification steps can be repeated for the remaining second to sixth buffer inlet ports 202-206, so that the buffer management program can identify all concentrated buffer solutions and the entire arrangement of the buffer inlet ports 201-206 of the manifold 23, so that when a given one of the buffer inlet ports 201-06 is opened and the buffer pump 191 is operated, the control unit 100 has identified which concentrated buffer solution is drawn through the manifold 23. The identity of this arrangement may be stored in the data storage device 109 for later use. In embodiments, the buffer management program may be configured to overwrite the concentrated buffer connection data stored in the data storage device 109 or store previous arrangements in a time-stamped historical database according to previous uses of the buffer management system 20.

Referring to fig. 18, in an embodiment of a process of identifying the arrangement of different biocontainers 55 in fluid communication with the plurality of buffer outlet ports 211-216 of the manifold 23 of the buffer management system 23 following the principles of the present disclosure, the control unit 100 may be used to sequentially place the manifold 23 at the first through sixth buffer fill positions to determine which surge biocontainer 55 in the diluted buffer rack towers 28, 29 receives the buffer solution discharged through the first through sixth buffer outlet ports 211-216, respectively.

In an embodiment, buffer discharge ports 211-216 of manifold 23 are in fluid communication with different ones of surge biocontainers 55 of

dilute buffer tower

28, 29, respectively. In fig. 18, the set of surge biocontainers 55 of the diluted buffer rack towers 28, 29 are connected to the first through sixth buffer outlet ports 211-216 in an unrelated manner unknown to the buffer management procedure (i.e., for example, the second surge biocontainer 55 "is connected to the first buffer outlet port 211 of manifold 23).

The identification module of the buffer management program is configured to sequentially drain fluid through each of the buffer drain ports 211-216 to identify which of the biological containers 55 is connected to which of the buffer drain ports 211211. The identification module of the buffer management program may sequentially place the manifold 23 at the first through sixth buffer fill positions to systematically identify which of the set of surge vessels 55 of the dilute buffer rack towers 28, 29 is connected to which of the first through sixth buffer outlet ports 211-216.

In an embodiment, the identification module of the buffer management program may be configured to automatically identify the biocontainer 55 with which each of the buffer drain ports 211-216 is in fluid communication based on the change in the fill level signal therefrom. In an embodiment, a suitable fill level sensor L01-L06 is associated with each of the surge biocontainers 55, respectively. Each of the fill level sensors L01-L06 is in electrical communication with the control unit 100 for transmitting a respective fill level signal thereto. Each fill level sensor L01-L06 is configured to detect an amount of material within surge biocontainer 55 and generate a fill level signal indicative of the detected amount of material. In an embodiment, the fill level sensors L01-L06 may be of any suitable type, such as capacitive fill level sensors or retransmission sensors, for example. In an embodiment, the identity of the particular surge biocontainer 55 receiving buffer solution from each of the first through sixth buffer inlet ports 211-216 may be determined by monitoring the respective each fill level signal received from each associated fill level sensor L01-L06. The identities (e.g., top-to-bottom L01 to L06) of the different fill level sensors L01-L06 (and thus the different surge biocontainers 55) of the diluted

buffer tower

28, 29 are controlled by the control unit 100 of the dilution skid, so that the buffer management program is configured to identify from which fill level sensor L01-L06 a given fill level signal is transmitted.

The identification module of the buffer management program may be configured to identify which of the surge biocontainers 55 is fluidly connected to the first buffer outlet port 211, and thus the particular one of the surge biocontainers in the set of surge biocontainers 55 of the diluted

buffer tower

28, 29, in which the diluted third buffer solution is stored, by monitoring the fill level signal during the first buffer fill position. In an embodiment, the identification module may determine which of the surge biocontainers 55 is fluidly connected to the first buffer outlet port 211, and thus the surge biocontainer in which the diluted third buffer solution in the set of surge biocontainers 55 is stored, by monitoring the change in the fill level signal received from the surge container 55 (i.e., the fill level sensors L01-L06 indicate an increase in liquid stored in its associated surge biocontainer 55 during the first buffer fill sequence).

In the illustrated embodiment, the identification module is configured to identify the second surge biocontainer 55 "as one of the set of surge biocontainer sets 55 in fluid communication with the first buffer outlet port 211, as the second fill level signal from the second surge biocontainer 55" and received by the control unit 100 changes (increases) as the diluted third buffer solution is drained from the first buffer outlet port 211.

In an embodiment, the control unit 100 may be configured to control the operation of the buffer management system such that the filling level of the other surge vessel 55 does not change during this identification process. The identification module of the buffer management program is configured to logically store the identity of the surge biocontainer 55 "fluidly connected to the first buffer outlet port 211 in the data storage device 109 so that this information can be retrieved by the buffer management program for later use.

The above-described identification steps can be repeated for the remaining second through sixth buffer fill positions so that the buffer management program can identify the overall arrangement of surge biocontainers 55 of the diluted buffer rack towers 28, 29 and associated buffer outlet ports 212-216 of the manifold 23, each of which is identified and stored in the data storage device 109 for subsequent use. In embodiments, the buffer management program may be configured to overwrite surge biocontainer connection data stored in data storage device 109, or store previous arrangements in a time-stamped historical database, according to previous uses of the buffer management system.

In an embodiment, the buffer management program undergoes a sequence that controls the control valves to place the manifold 23 in the first buffer stable position, as shown in fig. 10. Control unit 100 operates buffer pump 191 and WFI pump 192 such that the third concentrated buffer solution (from the previous identification of the concentrated buffer, the buffer management program can retrieve concentrated buffer 3 from data storage device 109 in fluid communication with first buffer inlet port 201, as depicted in fig. 17) and can operate the online dilution skid such that the third concentrated buffer is diluted online with WFI. The fluid mixture is pumped through the in-line conductivity and

pH sensors

171, 173 and then pumped down to the waste outlet port 217 until the third concentrated buffer solution is diluted to its operating concentration (i.e., 1 x) and is in specification according to the value detected by the

sensors

171, 173.

In an embodiment, the buffer management program may be configured to undergo a sequence that controls the control valves to place the manifold 23 in the first buffer fill position, as shown in fig. 18. Buffer pump 191 and WFI pump 192 continue to draw the third concentrated buffer solution and WFI through manifold 23 and out first buffer outlet port 211. The buffer management program may be configured to determine that the buffer discharged from the first buffer outlet port 211 is within the specifications of the third dilution buffer formulation based on the pH/conductivity "fingerprint" sensed by the in-

line sensors

171, 173.

Referring to fig. 19, in an embodiment, the identification module of the buffer management program is configured to automatically identify which of the unit inlet ports 301-07 of the bioprocessing unit 24 each of the biocontainers 55 of the diluted

buffer tower

28, 29 is in fluid communication based on the change in the fill level signal therefrom. The identification module of the buffer management program is configured to store in the data storage device 109 the identity of which of the unit inlets 301-07 of the biological processing unit 24 each of the biological receptacles 55 is fluidly connected to.

In an embodiment of a process of identifying an arrangement of biological vessels 55 in fluid communication with a plurality of

inlet ports

301, 302, 304-307 of a biological processing unit 24 following the principles of the present disclosure, the control unit 100 may be used to determine which surge biological vessel 55 of a dilute

buffer rack tower

28, 29 is discharging buffer solution to the respective

unit inlet port

301, 302, 304-307 of the biological processing unit 24. In an embodiment, the identification module of the buffer management program may be configured to identify which

inlet port

301, 302, 304-07 of the biological processing unit 24 receives which buffer solution stored in the dilute

buffer rack tower

28, 29.

In fig. 19, the set of surge biocontainers 55 of diluted

buffer tower

28, 29 are connected to six

unit inlet ports

301, 302, 304-307 of biological processing unit 24 in an unrelated manner (i.e., for example, second surge biocontainer 55 is connected to fourth unit inlet port 304 of biological processing unit 24) where the buffer management program is unknown or otherwise available from data storage device 109.

The identification module of the buffer management program may be configured to identify which of the surge biocontainers 55 "is fluidly connected to the fourth unit inlet port 304 by monitoring the fill level signal, and thus the particular surge biocontainer of the set of surge biocontainers 55" of the

dilute buffer tower

28, 29 from which the diluted third buffer solution will be provided to the biological processing unit 24 through the fourth unit inlet port 304. In an embodiment, the identification module may determine which of the surge biological containers 55 ″ is fluidly connected to the fourth unit inlet port 304 by monitoring changes in the fill level signal received from the surge container 55 during a fourth buffer inlet process in which the biological processing unit 24 is operated to draw buffer solution into it through the fourth unit inlet port 304 (i.e., the fill level sensors L01-L06 indicate a reduction in the liquid stored within its associated surge biological container 55 during the fourth buffer inlet process).

The identification module of the buffer management program may be configured to sequentially draw buffer solution from the set of surge bio-containers 55 through the identified one of the

unit inlet ports

301, 302, 304-307 of the biological processing unit 24 to systematically identify which of the surge containers 55 of the dilute buffer rack towers 28, 29 is fluidly connected to which of the

unit inlet ports

301, 302, 304-307 of the biological processing unit 24 based on changes in the fill level signal received from the particular surge container 55 of the dilute buffer rack towers 28, 29. The correlation between the second surge tank 55 "and the fourth inlet port 304 of the biological processing unit 24 may be sent to the control unit 100 of the dilution skid via the communication link established between the two.

In an embodiment, control unit 100 of dilution skid 30 is in communication with the control system of biological treatment unit 24. After the buffer is transferred from the second surge biocontainer 55 "to the biological processing unit 24, the control unit 100 of the dilution skid 30 detects the level change in the second buffer biocontainer 55" and identifies which buffer is just being transferred to the biological processing unit 24 (e.g., buffer 3 based on the process of fig. 18). This information is passed from the control unit 100 to the control system of the bio-processing unit 24. At the same time, the control system of the bio-processing unit 24 identifies which inlet valve is open (e.g., 304) and links the two bits of information together (i.e., buffer 3 linked to port 304).

In an embodiment, the level sensor of the surge bag rack is directly and physically linked to the control system of the bio-processing unit 24, and this system has an internally programmed location of the level sensors L01-L06 (top to bottom). The level change and inlet port information is then obtained directly by the control system of the bio-processing unit 24. In other embodiments, control unit 100 comprises a centralized monitoring system that is global and common to both dilution skid 30 and biological treatment unit 24.

In the illustrated embodiment, biological treatment unit 24 comprises a simulated moving bed chromatography unit. In other embodiments, biological treatment unit 24 may include any suitable unit operation skid that uses a variety of buffers for its operation and may be "buffer inlet independent" (i.e., the buffer inlets are not pre-dispensed for any particular buffer).

In the illustrated embodiment, the biological treatment unit 24 is operated such that the fourth inlet 304 is opened to introduce buffer solution from the second buffered biological container bag 55 ". In an embodiment, the biological processing unit 24 may communicate to the control unit 100 that the fourth unit inlet 304 is requesting buffer solution from the diluted

buffer rack tower

28, 29. The identification module may be configured to determine which of the surge biocontainers 55 "is fluidly connected to the fourth unit inlet 304 of the biological processing unit 24 by monitoring changes in the fill level signals received from the fill level sensors L01-L06 associated with the surge container 55. In the illustrated embodiment, because the fill level signal from the second surge biocontainer 55 "and received by control unit 100 changes as the third buffer solution drains from the second surge biocontainer 55" to the fourth unit inlet port 304 of biological treatment unit 24, the identification module may identify the second surge biocontainer 55 "as one of the set of surge biocontainers 55 in fluid communication with the fourth unit inlet port 304. In an embodiment, the control unit 100 may be configured to control the operation of the buffer management system 20 such that the filling level of the other surge vessels does not undergo a change during this identification process. The identification module of the buffer management program may be configured to store the identity of the surge biocontainer 55 "fluidly connected to the fourth unit inlet port 304 of the biological processing unit 24 in the data storage device 109 in a logical manner such that this information may be retrieved by the buffer management program for later use.

The above-described identification steps can be repeated for the other

unit inlet ports

301, 302, 304-07 of bioprocessing unit 24 so that the buffer management program can identify the overall arrangement of surge biocontainer 55 and associated

inlet ports

301, 302, 304-07 of bioprocessing unit 24, with each such identified arrangement being identified and stored in data storage device 109 for subsequent use. In embodiments, the buffer management program may be configured to overwrite the bioprocessing unit connection data stored in the data storage device 109 or store previous arrangements in a time-stamped historical database according to previous uses of the buffer management system 20.

In embodiments, the identification module may be used for other identification applications. For example, in an embodiment, an identification module constructed in accordance with the principles of the present disclosure may be used in any system that manages and dispenses buffers to another operating system. In an embodiment, the in-line dilution skid is made for re-use and is made of a suitable material for that purpose, for example stainless steel. In an embodiment, the bio-container assembly of the diluted buffer tower comprises different types of fill level sensors (such as e.g. a load cell or a scale).

All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," and "including" are to be construed as open-ended terms (i.e., meaning "including, but not limited to,") unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

1. A buffer management system, comprising:

a collection of concentrated buffer solutions;

an in-line dilution skid comprising a single-use manifold comprising a plurality of buffer inlet ports in fluid communication with respective different buffer solutions of a set of concentrated buffer solutions and a buffer characteristic sensor in fluid communication with each buffer inlet port, the buffer characteristic sensor configured to detect a value of a buffer characteristic of a fluid flowing therethrough and generate a buffer characteristic signal indicative of the buffer characteristic;

a control unit comprising a processor in electrical communication with the buffer characteristic sensor to receive a buffer characteristic signal therefrom, a non-transitory computer readable medium carrying a buffer management program, the processor programmed with the buffer management program, and a data storage device operably arranged with the processor, the buffer management program having an identification module configured to automatically identify a concentrated buffer solution entering the manifold via one of the buffer inlet ports and passing through the manifold based on the buffer characteristic signal.

2. The buffer management system of claim 1, wherein the data storage device comprises buffer characteristic data for a plurality of buffer recipes and the identification module of the buffer management program is configured to identify the concentrated buffer solution flowing through the manifold by analyzing the buffer characteristic signals to determine one of the buffer recipes that most closely matches the buffer characteristic signals.

3. The buffer management system of claim 2, wherein the control unit comprises a Human Machine Interface (HMI), and wherein the buffer management program comprises a recipe manager module configured to store buffer solution characteristic data for at least one buffer recipe in the data storage device for use by the identification module.

4. The buffer management system of any of claims 1-3, wherein the buffer characteristic sensor, the buffer characteristic, and the buffer characteristic signal comprise a first buffer characteristic sensor, a first buffer characteristic, and a first buffer characteristic signal, respectively, and wherein the single-use manifold comprises a second buffer characteristic sensor configured to detect a value of a second buffer characteristic of the fluid flowing therethrough and generate a second buffer characteristic signal indicative of the sensed value of the second buffer characteristic, the second buffer characteristic being different from the first buffer characteristic, wherein the buffer formulations stored in the data storage device each comprise buffer solution characteristic data for the first buffer characteristic and the second buffer characteristic, and wherein the identification module of the buffer management program is configured to identify the concentrated buffer solution flowing through the manifold based on the values of both the first buffer characteristic signal and the second buffer characteristic sensor.

5. The buffer management system of claim 4, wherein the first buffer characteristic and the second buffer characteristic comprise conductivity and pH, respectively.

6. The buffer management system of any of claims 1 to 3, wherein the identification module of the buffer management program is configured to draw the concentrated buffer solutions sequentially through each buffer inlet port to identify which of the set of concentrated buffer solutions is connected to which of the buffer inlet ports.

7. The buffer management system of claim 6, wherein the identification module of the buffer management program is configured to store in the data storage device the identity of the concentrated buffer solution fluidly connected to each buffer inlet port.

8. The buffer management system of any of claims 1 to 3, wherein the manifold comprises a plurality of buffer drain ports, the buffer management system further comprising:

a plurality of biological containers corresponding to a number of sets of concentrated buffer solutions, the plurality of buffer discharge ports being in fluid communication with different ones of the plurality of biological containers, respectively;

a plurality of fill level sensors respectively associated with one of the plurality of biocontainers, each fill level sensor configured to detect an amount of material within a biocontainer bag and generate a fill level signal indicative of the detected amount of material, each fill level sensor in electrical communication with the control unit to transmit a respective fill level signal thereto;

wherein the identification module of the buffer management program is configured to automatically identify the biocontainer in fluid communication with each buffer discharge port based on a change in the fill level signal therefrom.

9. The buffer management system of claim 8, wherein the identification module of the buffer management program is configured to sequentially drain fluid through each buffer drain port to identify which of the biocontainers is connected to which of the buffer drain ports.

10. The buffer management system of claim 9, wherein the identification module of the buffer management program is configured to store in the data storage device the identity of the biocontainer fluidly connected to each buffer drain port.

11. The buffer management system of claim 8, further comprising:

a biological treatment unit comprising a plurality of unit inlet ports in fluid communication with the plurality of biological containers, respectively;

wherein the identification module of the buffer management program is configured to automatically identify the cell inlet port with which each biocontainer is in fluid communication based on a change in the fill level signal therefrom.

12. The buffer management system of claim 11, wherein the identification module of the buffer management program is configured to store in the data storage device the identity of the biological receptacle fluidically connected to each unit inlet port of the biological processing unit.

13. A method of using a buffer management system, the method comprising:

drawing one of a set of amounts of concentrated buffer solution into a first buffer inlet port of a plurality of buffer inlet ports of a manifold;

sensing a buffer characteristic of the concentrated buffer solution in the manifold;

transmitting a buffer characteristic signal indicative of the value of the sensed buffer characteristic to a control unit;

identifying, using the control unit, a concentrated buffer solution entering the manifold via the first buffer inlet port based on the buffer characteristic signal;

sequentially drawing a respective other of a set of amounts of concentrated buffer solution into each other buffer inlet port of the plurality of buffer inlet ports of the manifold;

sequentially sensing a buffer characteristic of a respective other of the collection of concentrated buffer solutions in a manifold;

sequentially transmitting a buffer characteristic signal indicative of a value of a sensed buffer characteristic of a respective other one of the set of concentrated buffer solutions to the control unit;

sequentially identifying, using the control unit, a respective other of the set of concentrated buffer solutions entering the manifold via another of the plurality of buffer inlet ports of the manifold based on the buffer characteristic signal;

storing in the data storage device the identity of the concentrated buffer solution in fluid connection with each buffer inlet port.

14. The method of claim 13, further comprising:

loading buffer solution characteristic data of a plurality of buffer solution formulas in a data storage device;

wherein the control unit identifies the concentrated buffer solution flowing through the manifold by analyzing the buffer characteristic signal to determine one of the buffer formulations in the storage device that most closely matches the buffer characteristic signal.

15. The method of claim 13 or claim 14, wherein the buffer characteristic and the buffer characteristic signal comprise a first buffer characteristic and a first buffer characteristic signal, respectively, the method further comprising:

sensing a second buffer characteristic of the concentrated buffer solution in the manifold, the second buffer characteristic being different from the first buffer characteristic;

transmitting a second buffer characteristic signal indicative of the sensed value of the second buffer characteristic to the control unit;

wherein the control unit identifies the concentrated buffer solution entering the manifold via the first buffer inlet port based on the first buffer characteristic signal and the second buffer characteristic signal.

16. The method of claim 15, wherein the first buffer characteristic and the second buffer characteristic comprise conductivity and pH, respectively.

17. A method of using a buffer management system, the method comprising:

discharging a volume of liquid from a first buffer discharge port of a plurality of buffer discharge ports of a manifold into one of a plurality of biocontainers, the plurality of buffer discharge ports each in fluid communication with another of the plurality of biocontainers;

sensing an amount of material stored within each of the plurality of biocontainers, respectively;

transmitting a fill level signal to the control unit, respectively, the fill level signal being indicative of a value of the amount of material sensed within each of the plurality of biocontainers;

the control unit is used to identify the biocontainer with which the first buffer drain port is in fluid communication based on a change in the fill level signal therefrom.

18. The method of claim 17, further comprising:

sequentially discharging fluid through each buffer discharge port;

sequentially identifying, using the control unit, the biocontainers with which each buffer drain port is in fluid communication based on changes in the fill level signal therefrom;

storing in a data storage device the identity of the biocontainer fluidly connected to each buffer fluid outlet port.

19. The method of claim 18, further comprising:

sequentially discharging an amount of liquid from each of the biocontainers into a respective one of a plurality of cell inlet ports of a bioprocessing unit, the plurality of biocontainers being respectively in fluid communication with another cell inlet port of the bioprocessing unit;

sequentially using the control unit to identify the biocontainers in fluid communication with each unit inlet port based on the change in the fill level signal therefrom.